Daily Papers

The diverse nature of protein prediction tasks has traditionally necessitated specialized models, hindering the development of broadly applicable and computationally efficient Protein Language Models (PLMs). In this work, we introduce Prot2Token, a unified framework that overcomes these challenges by converting a wide spectrum of protein-related predictions, from sequence-level properties and residue-specific attributes to complex inter-protein interactions, into a standardized next-token prediction format. At its core, Prot2Token employs an autoregressive decoder, conditioned on embeddings from pre-trained protein encoders and guided by learnable task tokens, to perform diverse predictions. This architecture uniquely facilitates multi-task learning, enabling a single model to master numerous tasks with improved efficiency. We present extensive experimental validation across a variety of benchmarks, demonstrating Prot2Tokens strong predictive power in different types of protein-prediction tasks. Key results include significant speedups (e.g., near 1000x over AlphaFold2 with MSA) and performance often matching or exceeding specialized approaches. Beyond that, we introduce an auxiliary self-supervised decoder pre-training approach to improve spatially sensitive task performance. Prot2Token thus offers a significant step towards a versatile, high-throughput paradigm for protein modeling, promising to accelerate biological discovery and the development of novel therapeutics. The code is available at https://github.com/mahdip72/prot2token .

The parallels between protein sequences and natural language in their sequential structures have inspired the application of large language models (LLMs) to protein understanding. Despite the success of LLMs in NLP, their effectiveness in comprehending protein sequences remains an open question, largely due to the absence of datasets linking protein sequences to descriptive text. Researchers have then attempted to adapt LLMs for protein understanding by integrating a protein sequence encoder with a pre-trained LLM. However, this adaptation raises a fundamental question: "Can LLMs, originally designed for NLP, effectively comprehend protein sequences as a form of language?" Current datasets fall short in addressing this question due to the lack of a direct correlation between protein sequences and corresponding text descriptions, limiting the ability to train and evaluate LLMs for protein understanding effectively. To bridge this gap, we introduce ProteinLMDataset, a dataset specifically designed for further self-supervised pretraining and supervised fine-tuning (SFT) of LLMs to enhance their capability for protein sequence comprehension. Specifically, ProteinLMDataset includes 17.46 billion tokens for pretraining and 893,000 instructions for SFT. Additionally, we present ProteinLMBench, the first benchmark dataset consisting of 944 manually verified multiple-choice questions for assessing the protein understanding capabilities of LLMs. ProteinLMBench incorporates protein-related details and sequences in multiple languages, establishing a new standard for evaluating LLMs' abilities in protein comprehension. The large language model InternLM2-7B, pretrained and fine-tuned on the ProteinLMDataset, outperforms GPT-4 on ProteinLMBench, achieving the highest accuracy score. The dataset and the benchmark are available at https://huggingface.co/datasets/tsynbio/ProteinLMBench.

Predicting drug-target interaction (DTI) is critical in the drug discovery process. Despite remarkable advances in recent DTI models through the integration of representations from diverse drug and target encoders, such models often struggle to capture the fine-grained interactions between drugs and protein, i.e. the binding of specific drug atoms (or substructures) and key amino acids of proteins, which is crucial for understanding the binding mechanisms and optimising drug design. To address this issue, this paper introduces a novel model, called FusionDTI, which uses a token-level Fusion module to effectively learn fine-grained information for Drug-Target Interaction. In particular, our FusionDTI model uses the SELFIES representation of drugs to mitigate sequence fragment invalidation and incorporates the structure-aware (SA) vocabulary of target proteins to address the limitation of amino acid sequences in structural information, additionally leveraging pre-trained language models extensively trained on large-scale biomedical datasets as encoders to capture the complex information of drugs and targets. Experiments on three well-known benchmark datasets show that our proposed FusionDTI model achieves the best performance in DTI prediction compared with seven existing state-of-the-art baselines. Furthermore, our case study indicates that FusionDTI could highlight the potential binding sites, enhancing the explainability of the DTI prediction.

Learning effective protein representations is critical in a variety of tasks in biology such as predicting protein function or structure. Existing approaches usually pretrain protein language models on a large number of unlabeled amino acid sequences and then finetune the models with some labeled data in downstream tasks. Despite the effectiveness of sequence-based approaches, the power of pretraining on known protein structures, which are available in smaller numbers only, has not been explored for protein property prediction, though protein structures are known to be determinants of protein function. In this paper, we propose to pretrain protein representations according to their 3D structures. We first present a simple yet effective encoder to learn the geometric features of a protein. We pretrain the protein graph encoder by leveraging multiview contrastive learning and different self-prediction tasks. Experimental results on both function prediction and fold classification tasks show that our proposed pretraining methods outperform or are on par with the state-of-the-art sequence-based methods, while using much less pretraining data. Our implementation is available at https://github.com/DeepGraphLearning/GearNet.

Protein language models (PLMs) have emerged as powerful tools to detect complex patterns of protein sequences. However, the capability of PLMs to fully capture information on protein sequences might be limited by focusing on single pre-training tasks. Although adding data modalities or supervised objectives can improve the performance of PLMs, pre-training often remains focused on denoising corrupted sequences. To push the boundaries of PLMs, our research investigated a multi-task pre-training strategy. We developed Ankh3, a model jointly optimized on two objectives: masked language modeling with multiple masking probabilities and protein sequence completion relying only on protein sequences as input. This multi-task pre-training demonstrated that PLMs can learn richer and more generalizable representations solely from protein sequences. The results demonstrated improved performance in downstream tasks, such as secondary structure prediction, fluorescence, GB1 fitness, and contact prediction. The integration of multiple tasks gave the model a more comprehensive understanding of protein properties, leading to more robust and accurate predictions.

Protein modeling is an increasingly popular area of machine learning research. Semi-supervised learning has emerged as an important paradigm in protein modeling due to the high cost of acquiring supervised protein labels, but the current literature is fragmented when it comes to datasets and standardized evaluation techniques. To facilitate progress in this field, we introduce the Tasks Assessing Protein Embeddings (TAPE), a set of five biologically relevant semi-supervised learning tasks spread across different domains of protein biology. We curate tasks into specific training, validation, and test splits to ensure that each task tests biologically relevant generalization that transfers to real-life scenarios. We benchmark a range of approaches to semi-supervised protein representation learning, which span recent work as well as canonical sequence learning techniques. We find that self-supervised pretraining is helpful for almost all models on all tasks, more than doubling performance in some cases. Despite this increase, in several cases features learned by self-supervised pretraining still lag behind features extracted by state-of-the-art non-neural techniques. This gap in performance suggests a huge opportunity for innovative architecture design and improved modeling paradigms that better capture the signal in biological sequences. TAPE will help the machine learning community focus effort on scientifically relevant problems. Toward this end, all data and code used to run these experiments are available at https://github.com/songlab-cal/tape.

Pre-trained LLMs have demonstrated substantial capabilities across a range of conventional natural language processing (NLP) tasks, such as summarization and entity recognition. In this paper, we explore the application of LLMs in the generation of high-quality protein sequences. Specifically, we adopt a suite of pre-trained LLMs, including Mistral-7B1, Llama-2-7B2, Llama-3-8B3, and gemma-7B4, to produce valid protein sequences. All of these models are publicly available.5 Unlike previous work in this field, our approach utilizes a relatively small dataset comprising 42,000 distinct human protein sequences. We retrain these models to process protein-related data, ensuring the generation of biologically feasible protein structures. Our findings demonstrate that even with limited data, the adapted models exhibit efficiency comparable to established protein-focused models such as ProGen varieties, ProtGPT2, and ProLLaMA, which were trained on millions of protein sequences. To validate and quantify the performance of our models, we conduct comparative analyses employing standard metrics such as pLDDT, RMSD, TM-score, and REU. Furthermore, we commit to making the trained versions of all four models publicly available, fostering greater transparency and collaboration in the field of computational biology.

Learning effective protein representations is critical in a variety of tasks in biology such as predicting protein functions. Recent sequence representation learning methods based on Protein Language Models (PLMs) excel in sequence-based tasks, but their direct adaptation to tasks involving protein structures remains a challenge. In contrast, structure-based methods leverage 3D structural information with graph neural networks and geometric pre-training methods show potential in function prediction tasks, but still suffers from the limited number of available structures. To bridge this gap, our study undertakes a comprehensive exploration of joint protein representation learning by integrating a state-of-the-art PLM (ESM-2) with distinct structure encoders (GVP, GearNet, CDConv). We introduce three representation fusion strategies and explore different pre-training techniques. Our method achieves significant improvements over existing sequence- and structure-based methods, setting new state-of-the-art for function annotation. This study underscores several important design choices for fusing protein sequence and structure information. Our implementation is available at https://github.com/DeepGraphLearning/ESM-GearNet.

Recently, extensive deep learning architectures and pretraining strategies have been explored to support downstream protein applications. Additionally, domain-specific models incorporating biological knowledge have been developed to enhance performance in specialized tasks. In this work, we introduce Protap, a comprehensive benchmark that systematically compares backbone architectures, pretraining strategies, and domain-specific models across diverse and realistic downstream protein applications. Specifically, Protap covers five applications: three general tasks and two novel specialized tasks, i.e., enzyme-catalyzed protein cleavage site prediction and targeted protein degradation, which are industrially relevant yet missing from existing benchmarks. For each application, Protap compares various domain-specific models and general architectures under multiple pretraining settings. Our empirical studies imply that: (i) Though large-scale pretraining encoders achieve great results, they often underperform supervised encoders trained on small downstream training sets. (ii) Incorporating structural information during downstream fine-tuning can match or even outperform protein language models pretrained on large-scale sequence corpora. (iii) Domain-specific biological priors can enhance performance on specialized downstream tasks. Code and datasets are publicly available at https://github.com/Trust-App-AI-Lab/protap.

Current Large Language Models (LLMs) for understanding proteins primarily treats amino acid sequences as a text modality. Meanwhile, Protein Language Models (PLMs), such as ESM-2, have learned massive sequential evolutionary knowledge from the universe of natural protein sequences. Furthermore, structure-based encoders like ProteinMPNN learn the structural information of proteins through Graph Neural Networks. However, whether the incorporation of protein encoders can enhance the protein understanding of LLMs has not been explored. To bridge this gap, we propose EvoLlama, a multimodal framework that connects a structure-based encoder, a sequence-based protein encoder and an LLM for protein understanding. EvoLlama consists of a ProteinMPNN structure encoder, an ESM-2 protein sequence encoder, a multimodal projector to align protein and text representations and a Llama-3 text decoder. To train EvoLlama, we fine-tune it on protein-oriented instructions and protein property prediction datasets verbalized via natural language instruction templates. Our experiments show that EvoLlama's protein understanding capabilities have been significantly enhanced, outperforming other fine-tuned protein-oriented LLMs in zero-shot settings by an average of 1%-8% and surpassing the state-of-the-art baseline with supervised fine-tuning by an average of 6%. On protein property prediction datasets, our approach achieves promising results that are competitive with state-of-the-art task-specific baselines. We will release our code in a future version.

Current protein language models (PLMs) learn protein representations mainly based on their sequences, thereby well capturing co-evolutionary information, but they are unable to explicitly acquire protein functions, which is the end goal of protein representation learning. Fortunately, for many proteins, their textual property descriptions are available, where their various functions are also described. Motivated by this fact, we first build the ProtDescribe dataset to augment protein sequences with text descriptions of their functions and other important properties. Based on this dataset, we propose the ProtST framework to enhance Protein Sequence pre-training and understanding by biomedical Texts. During pre-training, we design three types of tasks, i.e., unimodal mask prediction, multimodal representation alignment and multimodal mask prediction, to enhance a PLM with protein property information with different granularities and, at the same time, preserve the PLM's original representation power. On downstream tasks, ProtST enables both supervised learning and zero-shot prediction. We verify the superiority of ProtST-induced PLMs over previous ones on diverse representation learning benchmarks. Under the zero-shot setting, we show the effectiveness of ProtST on zero-shot protein classification, and ProtST also enables functional protein retrieval from a large-scale database without any function annotation.

Motivation: Proteins are of great significance in living organisms. However, understanding their functions encounters numerous challenges, such as insufficient integration of multimodal information, a large number of training parameters, limited flexibility of classification-based methods, and the lack of systematic evaluation metrics for protein Q&A systems. To tackle these issues, we propose the Prot2Chat framework. Results: We modified ProteinMPNN to encode protein sequence and structural information in a unified way. We used a large language model (LLM) to encode questions into vectors and developed a protein-text adapter to compress protein information into virtual tokens based on these vectors, achieving the early fusion of text and protein information. Finally, the same LLM reads the virtual tokens and the questions to generate answers. To optimize training efficiency, we froze the encoder and employed Low-Rank Adaptation (LoRA) techniques for the LLM. Experiments on two datasets show that both automated metrics and expert evaluations demonstrate the superior performance of our model, and zero-shot prediction results highlight its generalization ability. The models and codes are available at https://github.com/ wangzc1233/Prot2Chat. Contact: [email protected] or [email protected] Key words: Protein Q&A, Early-Fusion, LLM

Existing works, including ELMO and BERT, have revealed the importance of pre-training for NLP tasks. While there does not exist a single pre-training model that works best in all cases, it is of necessity to develop a framework that is able to deploy various pre-training models efficiently. For this purpose, we propose an assemble-on-demand pre-training toolkit, namely Universal Encoder Representations (UER). UER is loosely coupled, and encapsulated with rich modules. By assembling modules on demand, users can either reproduce a state-of-the-art pre-training model or develop a pre-training model that remains unexplored. With UER, we have built a model zoo, which contains pre-trained models based on different corpora, encoders, and targets (objectives). With proper pre-trained models, we could achieve new state-of-the-art results on a range of downstream datasets.

Pre-trained text encoders have drawn sustaining attention in natural language processing (NLP) and shown their capability in obtaining promising results in different tasks. Recent studies illustrated that external self-supervised signals (or knowledge extracted by unsupervised learning, such as n-grams) are beneficial to provide useful semantic evidence for understanding languages such as Chinese, so as to improve the performance on various downstream tasks accordingly. To further enhance the encoders, in this paper, we propose to pre-train n-gram-enhanced encoders with a large volume of data and advanced techniques for training. Moreover, we try to extend the encoder to different languages as well as different domains, where it is confirmed that the same architecture is applicable to these varying circumstances and new state-of-the-art performance is observed from a long list of NLP tasks across languages and domains.

In recent years, protein-text models have gained significant attention for their potential in protein generation and understanding. Current approaches focus on integrating protein-related knowledge into large language models through continued pretraining and multi-modal alignment, enabling simultaneous comprehension of textual descriptions and protein sequences. Through a thorough analysis of existing model architectures and text-based protein understanding benchmarks, we identify significant data leakage issues present in current benchmarks. Moreover, conventional metrics derived from natural language processing fail to accurately assess the model's performance in this domain. To address these limitations, we reorganize existing datasets and introduce a novel evaluation framework based on biological entities. Motivated by our observation, we propose a retrieval-enhanced method, which significantly outperforms fine-tuned LLMs for protein-to-text generation and shows accuracy and efficiency in training-free scenarios. Our code and data can be seen at https://github.com/IDEA-XL/RAPM.

Pocket representations play a vital role in various biomedical applications, such as druggability estimation, ligand affinity prediction, and de novo drug design. While existing geometric features and pretrained representations have demonstrated promising results, they usually treat pockets independent of ligands, neglecting the fundamental interactions between them. However, the limited pocket-ligand complex structures available in the PDB database (less than 100 thousand non-redundant pairs) hampers large-scale pretraining endeavors for interaction modeling. To address this constraint, we propose a novel pocket pretraining approach that leverages knowledge from high-resolution atomic protein structures, assisted by highly effective pretrained small molecule representations. By segmenting protein structures into drug-like fragments and their corresponding pockets, we obtain a reasonable simulation of ligand-receptor interactions, resulting in the generation of over 5 million complexes. Subsequently, the pocket encoder is trained in a contrastive manner to align with the representation of pseudo-ligand furnished by some pretrained small molecule encoders. Our method, named ProFSA, achieves state-of-the-art performance across various tasks, including pocket druggability prediction, pocket matching, and ligand binding affinity prediction. Notably, ProFSA surpasses other pretraining methods by a substantial margin. Moreover, our work opens up a new avenue for mitigating the scarcity of protein-ligand complex data through the utilization of high-quality and diverse protein structure databases.

Predicting protein function from sequence is a central challenge in computational biology. While existing methods rely heavily on structured ontologies or similarity-based techniques, they often lack the flexibility to express structure-free functional descriptions and novel biological functions. In this work, we introduce Prot2Text-V2, a novel multimodal sequence-to-text model that generates free-form natural language descriptions of protein function directly from amino acid sequences. Our method combines a protein language model as a sequence encoder (ESM-3B) and a decoder-only language model (LLaMA-3.1-8B-Instruct) through a lightweight nonlinear modality projector. A key innovation is our Hybrid Sequence-level Contrastive Alignment Learning (H-SCALE), which improves cross-modal learning by matching mean- and std-pooled protein embeddings with text representations via contrastive loss. After the alignment phase, we apply instruction-based fine-tuning using LoRA on the decoder to teach the model how to generate accurate protein function descriptions conditioned on the protein sequence. We train Prot2Text-V2 on about 250K curated entries from SwissProt and evaluate it under low-homology conditions, where test sequences have low similarity with training samples. Prot2Text-V2 consistently outperforms traditional and LLM-based baselines across various metrics.

This paper introduces diffusion protein language model (DPLM), a versatile protein language model that demonstrates strong generative and predictive capabilities for protein sequences. We first pre-train scalable DPLMs from evolutionary-scale protein sequences within a generative self-supervised discrete diffusion probabilistic framework, which generalizes language modeling for proteins in a principled way. After pre-training, DPLM exhibits the ability to generate structurally plausible, novel, and diverse protein sequences for unconditional generation. We further demonstrate the proposed diffusion generative pre-training makes DPLM possess a better understanding of proteins, making it a superior representation learner, which can be fine-tuned for various predictive tasks, comparing favorably to ESM2 (Lin et al., 2022). Moreover, DPLM can be tailored for various needs, which showcases its prowess of conditional generation in several ways: (1) conditioning on partial peptide sequences, e.g., generating scaffolds for functional motifs with high success rate; (2) incorporating other modalities as conditioner, e.g., structure-conditioned generation for inverse folding; and (3) steering sequence generation towards desired properties, e.g., satisfying specified secondary structures, through a plug-and-play classifier guidance. Code is released at https://github.com/bytedance/dplm.

Protein language models are a powerful tool for learning protein representations through pre-training on vast protein sequence datasets. However, traditional protein language models lack explicit structural supervision, despite its relevance to protein function. To address this issue, we introduce the integration of remote homology detection to distill structural information into protein language models without requiring explicit protein structures as input. We evaluate the impact of this structure-informed training on downstream protein function prediction tasks. Experimental results reveal consistent improvements in function annotation accuracy for EC number and GO term prediction. Performance on mutant datasets, however, varies based on the relationship between targeted properties and protein structures. This underscores the importance of considering this relationship when applying structure-aware training to protein function prediction tasks. Code and model weights are available at https://github.com/DeepGraphLearning/esm-s.

Understanding the relationships between protein sequence, structure and function is a long-standing biological challenge with manifold implications from drug design to our understanding of evolution. Recently, protein language models have emerged as the preferred method for this challenge, thanks to their ability to harness large sequence databases. Yet, their reliance on expansive sequence data and parameter sets limits their flexibility and practicality in real-world scenarios. Concurrently, the recent surge in computationally predicted protein structures unlocks new opportunities in protein representation learning. While promising, the computational burden carried by such complex data still hinders widely-adopted practical applications. To address these limitations, we introduce a novel framework that enhances protein language models by integrating protein structural data. Drawing from recent advances in graph transformers, our approach refines the self-attention mechanisms of pretrained language transformers by integrating structural information with structure extractor modules. This refined model, termed Protein Structure Transformer (PST), is further pretrained on a small protein structure database, using the same masked language modeling objective as traditional protein language models. Empirical evaluations of PST demonstrate its superior parameter efficiency relative to protein language models, despite being pretrained on a dataset comprising only 542K structures. Notably, PST consistently outperforms the state-of-the-art foundation model for protein sequences, ESM-2, setting a new benchmark in protein function prediction. Our findings underscore the potential of integrating structural information into protein language models, paving the way for more effective and efficient protein modeling Code and pretrained models are available at https://github.com/BorgwardtLab/PST.

Protein language models (pLMs) pre-trained on vast protein sequence databases excel at various downstream tasks but lack the structural knowledge essential for many biological applications. To address this, we integrate structural insights from pre-trained protein graph neural networks (pGNNs) into pLMs through a latent-level contrastive learning task. This task aligns residue representations from pLMs with those from pGNNs across multiple proteins, enriching pLMs with inter-protein structural knowledge. Additionally, we incorporate a physical-level task that infuses intra-protein structural knowledge by optimizing pLMs to predict structural tokens. The proposed dual-task framework effectively incorporates both inter-protein and intra-protein structural knowledge into pLMs. Given the variability in the quality of protein structures in PDB, we further introduce a residue loss selection module, which uses a small model trained on high-quality structures to select reliable yet challenging residue losses for the pLM to learn. Applying our structure alignment method to the state-of-the-art ESM2 and AMPLIFY results in notable performance gains across a wide range of tasks, including a 12.7% increase in ESM2 contact prediction. The data, code, and resulting SaESM2 and SaAMPLIFY models will be released on Hugging Face.

We report a flexible language-model based deep learning strategy, applied here to solve complex forward and inverse problems in protein modeling, based on an attention neural network that integrates transformer and graph convolutional architectures in a causal multi-headed graph mechanism, to realize a generative pretrained model. The model is applied to predict secondary structure content (per-residue level and overall content), protein solubility, and sequencing tasks. Further trained on inverse tasks, the model is rendered capable of designing proteins with these properties as target features. The model is formulated as a general framework, completely prompt-based, and can be adapted for a variety of downstream tasks. We find that adding additional tasks yields emergent synergies that the model exploits in improving overall performance, beyond what would be possible by training a model on each dataset alone. Case studies are presented to validate the method, yielding protein designs specifically focused on structural proteins, but also exploring the applicability in the design of soluble, antimicrobial biomaterials. While our model is trained to ultimately perform 8 distinct tasks, with available datasets it can be extended to solve additional problems. In a broader sense, this work illustrates a form of multiscale modeling that relates a set of ultimate building blocks (here, byte-level utf8 characters) to complex output. This materiomic scheme captures complex emergent relationships between universal building block and resulting properties via a synergizing learning capacity to express a set of potentialities embedded in the knowledge used in training, via the interplay of universality and diversity.

Generative protein language models are a natural way to design new proteins with desired functions. However, current models are either difficult to direct to produce a protein from a specific family of interest, or must be trained on a large multiple sequence alignment (MSA) from the specific family of interest, making them unable to benefit from transfer learning across families. To address this, we propose Protein Evolutionary Transformer (PoET), an autoregressive generative model of whole protein families that learns to generate sets of related proteins as sequences-of-sequences across tens of millions of natural protein sequence clusters. PoET can be used as a retrieval-augmented language model to generate and score arbitrary modifications conditioned on any protein family of interest, and can extrapolate from short context lengths to generalize well even for small families. This is enabled by a unique Transformer layer; we model tokens sequentially within sequences while attending between sequences order invariantly, allowing PoET to scale to context lengths beyond those used during training. In extensive experiments on deep mutational scanning datasets, we show that PoET outperforms existing protein language models and evolutionary sequence models for variant function prediction across proteins of all MSA depths. We also demonstrate PoET's ability to controllably generate new protein sequences.

Recent research in representation learning utilizes large databases of proteins or molecules to acquire knowledge of drug and protein structures through unsupervised learning techniques. These pre-trained representations have proven to significantly enhance the accuracy of subsequent tasks, such as predicting the affinity between drugs and target proteins. In this study, we demonstrate that by incorporating knowledge graphs from diverse sources and modalities into the sequences or SMILES representation, we can further enrich the representation and achieve state-of-the-art results on established benchmark datasets. We provide preprocessed and integrated data obtained from 7 public sources, which encompass over 30M triples. Additionally, we make available the pre-trained models based on this data, along with the reported outcomes of their performance on three widely-used benchmark datasets for drug-target binding affinity prediction found in the Therapeutic Data Commons (TDC) benchmarks. Additionally, we make the source code for training models on benchmark datasets publicly available. Our objective in releasing these pre-trained models, accompanied by clean data for model pretraining and benchmark results, is to encourage research in knowledge-enhanced representation learning.

Protein language models have shown remarkable success in learning biological information from protein sequences. However, most existing models are limited by either autoencoding or autoregressive pre-training objectives, which makes them struggle to handle protein understanding and generation tasks concurrently. We propose a unified protein language model, xTrimoPGLM, to address these two types of tasks simultaneously through an innovative pre-training framework. Our key technical contribution is an exploration of the compatibility and the potential for joint optimization of the two types of objectives, which has led to a strategy for training xTrimoPGLM at an unprecedented scale of 100 billion parameters and 1 trillion training tokens. Our extensive experiments reveal that 1) xTrimoPGLM significantly outperforms other advanced baselines in 18 protein understanding benchmarks across four categories. The model also facilitates an atomic-resolution view of protein structures, leading to an advanced 3D structural prediction model that surpasses existing language model-based tools. 2) xTrimoPGLM not only can generate de novo protein sequences following the principles of natural ones, but also can perform programmable generation after supervised fine-tuning (SFT) on curated sequences. These results highlight the substantial capability and versatility of xTrimoPGLM in understanding and generating protein sequences, contributing to the evolving landscape of foundation models in protein science.

Pre-trained language models like ChatGPT have significantly improved code generation. As these models scale up, there is an increasing need for the output to handle more intricate tasks. Moreover, in bioinformatics, generating functional programs poses additional notable challenges due to the amount of domain knowledge, the need for complicated data operations, and intricate functional dependencies between the operations. Here, we present BioCoder, a benchmark developed to evaluate existing pre-trained models in generating bioinformatics code. In relation to function-code generation, BioCoder covers potential package dependencies, class declarations, and global variables. It incorporates 1026 functions and 1243 methods in Python and Java from GitHub and 253 examples from the Rosalind Project. BioCoder incorporates a fuzz-testing framework for evaluation, and we have applied it to evaluate many models including InCoder, CodeGen, CodeGen2, SantaCoder, StarCoder, StarCoder+, InstructCodeT5+, and ChatGPT. Our detailed analysis of these models emphasizes the importance of domain knowledge, pragmatic code generation, and contextual understanding. Our dataset, benchmark, Docker images, and scripts required for testing are all available at https://github.com/gersteinlab/biocoder.

Pre-trained encoder-decoder transformer architectures have become increasingly popular recently with the advent of T5 models. T5 has also become more favorable over other architectures like BERT due to the amount of data that it is pre-trained on, increased scale of model parameter sizes and easy applicability to a diverse set of tasks due to the generative nature of the model. While being able to generalize to a wide variety of tasks, it is not clear that encoder-decoder architectures are the most efficient for fine-tuning tasks that don't require auto-regressive decoding. In this work, we study fine-tuning pre-trained encoder-decoder models for tasks such as classification, multi-label classification, and structured prediction. We propose EncT5, a framework for these problems, and illustrate instantiations for these tasks. Our experiment results show that EncT5 has advantages over T5 such as efficiency and usability out performs BERT when evaluated on publicly available pre-trained checkpoints.

Offline model-based optimization aims to maximize a black-box objective function with a static dataset of designs and their scores. In this paper, we focus on biological sequence design to maximize some sequence score. A recent approach employs bidirectional learning, combining a forward mapping for exploitation and a backward mapping for constraint, and it relies on the neural tangent kernel (NTK) of an infinitely wide network to build a proxy model. Though effective, the NTK cannot learn features because of its parametrization, and its use prevents the incorporation of powerful pre-trained Language Models (LMs) that can capture the rich biophysical information in millions of biological sequences. We adopt an alternative proxy model, adding a linear head to a pre-trained LM, and propose a linearization scheme. This yields a closed-form loss and also takes into account the biophysical information in the pre-trained LM. In addition, the forward mapping and the backward mapping play different roles and thus deserve different weights during sequence optimization. To achieve this, we train an auxiliary model and leverage its weak supervision signal via a bi-level optimization framework to effectively learn how to balance the two mappings. Further, by extending the framework, we develop the first learning rate adaptation module Adaptive-eta, which is compatible with all gradient-based algorithms for offline model-based optimization. Experimental results on DNA/protein sequence design tasks verify the effectiveness of our algorithm. Our code is available~https://anonymous.4open.science/r/BIB-ICLR2023-Submission/README.md{here.}

Proteins are essential macromolecules defined by their amino acid sequences, which determine their three-dimensional structures and, consequently, their functions in all living organisms. Therefore, generative protein modeling necessitates a multimodal approach to simultaneously model, understand, and generate both sequences and structures. However, existing methods typically use separate models for each modality, limiting their ability to capture the intricate relationships between sequence and structure. This results in suboptimal performance in tasks that requires joint understanding and generation of both modalities. In this paper, we introduce DPLM-2, a multimodal protein foundation model that extends discrete diffusion protein language model (DPLM) to accommodate both sequences and structures. To enable structural learning with the language model, 3D coordinates are converted to discrete tokens using a lookup-free quantization-based tokenizer. By training on both experimental and high-quality synthetic structures, DPLM-2 learns the joint distribution of sequence and structure, as well as their marginals and conditionals. We also implement an efficient warm-up strategy to exploit the connection between large-scale evolutionary data and structural inductive biases from pre-trained sequence-based protein language models. Empirical evaluation shows that DPLM-2 can simultaneously generate highly compatible amino acid sequences and their corresponding 3D structures eliminating the need for a two-stage generation approach. Moreover, DPLM-2 demonstrates competitive performance in various conditional generation tasks, including folding, inverse folding, and scaffolding with multimodal motif inputs, as well as providing structure-aware representations for predictive tasks.

Inspired by the great success of Masked Language Modeling (MLM) in the natural language domain, the paradigm of self-supervised pre-training and fine-tuning has also achieved remarkable progress in the field of DNA sequence modeling. However, previous methods often relied on massive pre-training data or large-scale base models with huge parameters, imposing a significant computational burden. To address this, many works attempted to use more compact models to achieve similar outcomes but still fell short by a considerable margin. In this work, we propose a Hybrid Architecture Distillation (HAD) approach, leveraging both distillation and reconstruction tasks for more efficient and effective pre-training. Specifically, we employ the NTv2-500M as the teacher model and devise a grouping masking strategy to align the feature embeddings of visible tokens while concurrently reconstructing the invisible tokens during MLM pre-training. To validate the effectiveness of our proposed method, we conducted comprehensive experiments on the Nucleotide Transformer Benchmark and Genomic Benchmark. Compared to models with similar parameters, our model achieved excellent performance. More surprisingly, it even surpassed the distillation ceiling-teacher model on some sub-tasks, which is more than 500 times larger. Lastly, we utilize t-SNE for more intuitive visualization, which shows that our model can gain a sophisticated understanding of the intrinsic representation pattern in genomic sequences.

Predicting protein function from amino acid sequence remains a central challenge in data-scarce (low-N) regimes, limiting machine learning-guided protein design when only small amounts of assay-labeled sequence-function data are available. Protein language models (pLMs) have advanced the field by providing evolutionary-informed embeddings and sparse autoencoders (SAEs) have enabled decomposition of these embeddings into interpretable latent variables that capture structural and functional features. However, the effectiveness of SAEs for low-N function prediction and protein design has not been systematically studied. Herein, we evaluate SAEs trained on fine-tuned ESM2 embeddings across diverse fitness extrapolation and protein engineering tasks. We show that SAEs, with as few as 24 sequences, consistently outperform or compete with their ESM2 baselines in fitness prediction, indicating that their sparse latent space encodes compact and biologically meaningful representations that generalize more effectively from limited data. Moreover, steering predictive latents exploits biological motifs in pLM representations, yielding top-fitness variants in 83% of cases compared to designing with ESM2 alone.

The complex nature of big biological systems pushed some scientists to classify its understanding under the inconceivable missions. Different leveled challenges complicated this task, one of is the prediction of a protein's function. In recent years, significant progress has been made in this field through the development of various machine learning approaches. However, most existing methods formulate the task as a multi-classification problem, i.e assigning predefined labels to proteins. In this work, we propose a novel approach, Prot2Text, which predicts a protein function's in a free text style, moving beyond the conventional binary or categorical classifications. By combining Graph Neural Networks(GNNs) and Large Language Models(LLMs), in an encoder-decoder framework, our model effectively integrates diverse data types including proteins' sequences, structures, and textual annotations. This multimodal approach allows for a holistic representation of proteins' functions, enabling the generation of detailed and accurate descriptions. To evaluate our model, we extracted a multimodal protein dataset from SwissProt, and demonstrate empirically the effectiveness of Prot2Text. These results highlight the transformative impact of multimodal models, specifically the fusion of GNNs and LLMs, empowering researchers with powerful tools for more accurate prediction of proteins' functions. The code, the models and a demo will be publicly released.

Attention-based models trained on protein sequences have demonstrated incredible success at classification and generation tasks relevant for artificial intelligence-driven protein design. However, we lack a sufficient understanding of how very large-scale models and data play a role in effective protein model development. We introduce a suite of protein language models, named ProGen2, that are scaled up to 6.4B parameters and trained on different sequence datasets drawn from over a billion proteins from genomic, metagenomic, and immune repertoire databases. ProGen2 models show state-of-the-art performance in capturing the distribution of observed evolutionary sequences, generating novel viable sequences, and predicting protein fitness without additional finetuning. As large model sizes and raw numbers of protein sequences continue to become more widely accessible, our results suggest that a growing emphasis needs to be placed on the data distribution provided to a protein sequence model. We release the ProGen2 models and code at https://github.com/salesforce/progen.

Pretrained Transformer encoders are the dominant approach to sequence labeling. While some alternative architectures-such as xLSTMs, structured state-space models, diffusion models, and adversarial learning-have shown promise in language modeling, few have been applied to sequence labeling, and mostly on flat or simplified tasks. We study how these architectures adapt across tagging tasks that vary in structural complexity, label space, and token dependencies, with evaluation spanning multiple languages. We find that the strong performance previously observed in simpler settings does not always generalize well across languages or datasets, nor does it extend to more complex structured tasks.

Pre-trained Transformers (\eg BERT) have been commonly used in existing dense retrieval methods for parameter initialization, and recent studies are exploring more effective pre-training tasks for further improving the quality of dense vectors. Although various novel and effective tasks have been proposed, their different input formats and learning objectives make them hard to be integrated for jointly improving the model performance. In this work, we aim to unify a variety of pre-training tasks into the bottlenecked masked autoencoder manner, and integrate them into a multi-task pre-trained model, namely MASTER. Concretely, MASTER utilizes a shared-encoder multi-decoder architecture that can construct a representation bottleneck to compress the abundant semantic information across tasks into dense vectors. Based on it, we integrate three types of representative pre-training tasks: corrupted passages recovering, related passages recovering and PLMs outputs recovering, to characterize the inner-passage information, inter-passage relations and PLMs knowledge. Extensive experiments have shown that our approach outperforms competitive dense retrieval methods. Our code and data are publicly released in https://github.com/microsoft/SimXNS.

Using language models (LMs) pre-trained in a self-supervised setting on large corpora and then fine-tuning for a downstream task has helped to deal with the problem of limited label data for supervised learning tasks such as Named Entity Recognition (NER). Recent research in biomedical language processing has offered a number of biomedical LMs pre-trained using different methods and techniques that advance results on many BioNLP tasks, including NER. However, there is still a lack of a comprehensive comparison of pre-training approaches that would work more optimally in the biomedical domain. This paper aims to investigate different pre-training methods, such as pre-training the biomedical LM from scratch and pre-training it in a continued fashion. We compare existing methods with our proposed pre-training method of initializing weights for new tokens by distilling existing weights from the BERT model inside the context where the tokens were found. The method helps to speed up the pre-training stage and improve performance on NER. In addition, we compare how masking rate, corruption strategy, and masking strategies impact the performance of the biomedical LM. Finally, using the insights from our experiments, we introduce a new biomedical LM (BIOptimus), which is pre-trained using Curriculum Learning (CL) and contextualized weight distillation method. Our model sets new states of the art on several biomedical Named Entity Recognition (NER) tasks. We release our code and all pre-trained models

Pre-trained encoders are widely employed in dense prediction tasks for their capability to effectively extract visual features from images. The decoder subsequently processes these features to generate pixel-level predictions. However, due to structural differences and variations in input data, only encoders benefit from pre-learned representations from vision benchmarks such as image classification and self-supervised learning, while decoders are typically trained from scratch. In this paper, we introduce timesNet, which facilitates a "pre-trained encoder times pre-trained decoder" collaboration through three innovative designs. timesNet enables the direct utilization of pre-trained models within the decoder, integrating pre-learned representations into the decoding process to enhance performance in dense prediction tasks. By simply coupling the pre-trained encoder and pre-trained decoder, timesNet distinguishes itself as a highly promising approach. Remarkably, it achieves this without relying on decoding-specific structures or task-specific algorithms. Despite its streamlined design, timesNet outperforms advanced methods in tasks such as monocular depth estimation and semantic segmentation, achieving state-of-the-art performance particularly in monocular depth estimation. and semantic segmentation, achieving state-of-the-art results, especially in monocular depth estimation. embedding algorithms. Despite its streamlined design, timesNet outperforms advanced methods in tasks such as monocular depth estimation and semantic segmentation, achieving state-of-the-art performance particularly in monocular depth estimation.

We pretrain METAGENE-1, a 7-billion-parameter autoregressive transformer model, which we refer to as a metagenomic foundation model, on a novel corpus of diverse metagenomic DNA and RNA sequences comprising over 1.5 trillion base pairs. This dataset is sourced from a large collection of human wastewater samples, processed and sequenced using deep metagenomic (next-generation) sequencing methods. Unlike genomic models that focus on individual genomes or curated sets of specific species, the aim of METAGENE-1 is to capture the full distribution of genomic information present within this wastewater, to aid in tasks relevant to pandemic monitoring and pathogen detection. We carry out byte-pair encoding (BPE) tokenization on our dataset, tailored for metagenomic sequences, and then pretrain our model. In this paper, we first detail the pretraining dataset, tokenization strategy, and model architecture, highlighting the considerations and design choices that enable the effective modeling of metagenomic data. We then show results of pretraining this model on our metagenomic dataset, providing details about our losses, system metrics, and training stability over the course of pretraining. Finally, we demonstrate the performance of METAGENE-1, which achieves state-of-the-art results on a set of genomic benchmarks and new evaluations focused on human-pathogen detection and genomic sequence embedding, showcasing its potential for public health applications in pandemic monitoring, biosurveillance, and early detection of emerging health threats.

mRNA-based vaccines have become a major focus in the pharmaceutical industry. The coding sequence as well as the Untranslated Regions (UTRs) of an mRNA can strongly influence translation efficiency, stability, degradation, and other factors that collectively determine a vaccine's effectiveness. However, optimizing mRNA sequences for those properties remains a complex challenge. Existing deep learning models often focus solely on coding region optimization, overlooking the UTRs. We present Helix-mRNA, a structured state-space-based and attention hybrid model to address these challenges. In addition to a first pre-training, a second pre-training stage allows us to specialise the model with high-quality data. We employ single nucleotide tokenization of mRNA sequences with codon separation, ensuring prior biological and structural information from the original mRNA sequence is not lost. Our model, Helix-mRNA, outperforms existing methods in analysing both UTRs and coding region properties. It can process sequences 6x longer than current approaches while using only 10% of the parameters of existing foundation models. Its predictive capabilities extend to all mRNA regions. We open-source the model (https://github.com/helicalAI/helical) and model weights (https://huggingface.co/helical-ai/helix-mRNA).

Inspired by the success of unsupervised pre-training paradigms, researchers have applied these approaches to DNA pre-training. However, we argue that these approaches alone yield suboptimal results because pure DNA sequences lack sufficient information, since their functions are regulated by genomic profiles like chromatin accessibility. Here, we demonstrate that supervised training for genomic profile prediction serves as a more effective alternative to pure sequence pre-training. Furthermore, considering the multi-species and multi-profile nature of genomic profile prediction, we introduce our Species-Profile Adaptive Collaborative Experts (SPACE) that leverages Mixture of Experts (MoE) to better capture the relationships between DNA sequences across different species and genomic profiles, thereby learning more effective DNA representations. Through extensive experiments across various tasks, our model achieves state-of-the-art performance, establishing that DNA models trained with supervised genomic profiles serve as powerful DNA representation learners. The code is available at https://github.com/ZhuJiwei111/SPACE.

Generative machine learning models are increasingly being used to design novel proteins for therapeutic and biotechnological applications. However, the current methods mostly focus on the design of proteins with a fixed backbone structure, which leads to their limited ability to account for protein flexibility, one of the crucial properties for protein function. Learning to engineer protein flexibility is problematic because the available data are scarce, heterogeneous, and costly to obtain using computational as well as experimental methods. Our contributions to address this problem are three-fold. First, we comprehensively compare methods for quantifying protein flexibility and identify data relevant to learning. Second, we design and train flexibility predictors utilizing sequential or both sequential and structural information on the input. We overcome the data scarcity issue by leveraging a pre-trained protein language model. Third, we introduce a method for fine-tuning a protein inverse folding model to steer it toward desired flexibility in specified regions. We demonstrate that our method Flexpert-Design enables guidance of inverse folding models toward increased flexibility. This opens up new possibilities for protein flexibility engineering and the development of proteins with enhanced biological activities.

Large Language Models (LLMs) have revolutionized the field of natural language processing, but they fall short in comprehending biological sequences such as proteins. To address this challenge, we propose InstructProtein, an innovative LLM that possesses bidirectional generation capabilities in both human and protein languages: (i) taking a protein sequence as input to predict its textual function description and (ii) using natural language to prompt protein sequence generation. To achieve this, we first pre-train an LLM on both protein and natural language corpora, enabling it to comprehend individual languages. Then supervised instruction tuning is employed to facilitate the alignment of these two distinct languages. Herein, we introduce a knowledge graph-based instruction generation framework to construct a high-quality instruction dataset, addressing annotation imbalance and instruction deficits in existing protein-text corpus. In particular, the instructions inherit the structural relations between proteins and function annotations in knowledge graphs, which empowers our model to engage in the causal modeling of protein functions, akin to the chain-of-thought processes in natural languages. Extensive experiments on bidirectional protein-text generation tasks show that InstructProtein outperforms state-of-the-art LLMs by large margins. Moreover, InstructProtein serves as a pioneering step towards text-based protein function prediction and sequence design, effectively bridging the gap between protein and human language understanding.

Proteins are complex biomolecules that perform a variety of crucial functions within living organisms. Designing and generating novel proteins can pave the way for many future synthetic biology applications, including drug discovery. However, it remains a challenging computational task due to the large modeling space of protein structures. In this study, we propose a latent diffusion model that can reduce the complexity of protein modeling while flexibly capturing the distribution of natural protein structures in a condensed latent space. Specifically, we propose an equivariant protein autoencoder that embeds proteins into a latent space and then uses an equivariant diffusion model to learn the distribution of the latent protein representations. Experimental results demonstrate that our method can effectively generate novel protein backbone structures with high designability and efficiency.

Antibodies comprise the most versatile class of binding molecules, with numerous applications in biomedicine. Computational design of antibodies involves generating novel and diverse sequences, while maintaining structural consistency. Unique to antibodies, designing the complementarity-determining region (CDR), which determines the antigen binding affinity and specificity, creates its own unique challenges. Recent deep learning models have shown impressive results, however the limited number of known antibody sequence/structure pairs frequently leads to degraded performance, particularly lacking diversity in the generated sequences. In our work we address this challenge by leveraging Model Reprogramming (MR), which repurposes pretrained models on a source language to adapt to the tasks that are in a different language and have scarce data - where it may be difficult to train a high-performing model from scratch or effectively fine-tune an existing pre-trained model on the specific task. Specifically, we introduce ReprogBert in which a pretrained English language model is repurposed for protein sequence infilling - thus considers cross-language adaptation using less data. Results on antibody design benchmarks show that our model on low-resourced antibody sequence dataset provides highly diverse CDR sequences, up to more than a two-fold increase of diversity over the baselines, without losing structural integrity and naturalness. The generated sequences also demonstrate enhanced antigen binding specificity and virus neutralization ability. Code is available at https://github.com/IBM/ReprogBERT

Proteins are essential to life's processes, underpinning evolution and diversity. Advances in sequencing technology have revealed millions of proteins, underscoring the need for sophisticated pre-trained protein models for biological analysis and AI development. Facebook's ESM2, the most advanced protein language model to date, leverages a masked prediction task for unsupervised learning, crafting amino acid representations with notable biochemical accuracy. Yet, it lacks in delivering functional protein insights, signaling an opportunity for enhancing representation quality.Our study addresses this gap by incorporating protein family classification into ESM2's training.This approach, augmented with Community Propagation-Based Clustering Algorithm, improves global protein representations, while a contextual prediction task fine-tunes local amino acid accuracy. Significantly, our model achieved state-of-the-art results in several downstream experiments, demonstrating the power of combining global and local methodologies to substantially boost protein representation quality.

The goal of protein representation learning is to extract knowledge from protein databases that can be applied to various protein-related downstream tasks. Although protein sequence, structure, and function are the three key modalities for a comprehensive understanding of proteins, existing methods for protein representation learning have utilized only one or two of these modalities due to the difficulty of capturing the asymmetric interrelationships between them. To account for this asymmetry, we introduce our novel asymmetric multi-modal masked autoencoder (AMMA). AMMA adopts (1) a unified multi-modal encoder to integrate all three modalities into a unified representation space and (2) asymmetric decoders to ensure that sequence latent features reflect structural and functional information. The experiments demonstrate that the proposed AMMA is highly effective in learning protein representations that exhibit well-aligned inter-modal relationships, which in turn makes it effective for various downstream protein-related tasks.

We introduce a protein language model for determining the complete sequence of a peptide based on measurement of a limited set of amino acids. To date, protein sequencing relies on mass spectrometry, with some novel edman degregation based platforms able to sequence non-native peptides. Current protein sequencing techniques face limitations in accurately identifying all amino acids, hindering comprehensive proteome analysis. Our method simulates partial sequencing data by selectively masking amino acids that are experimentally difficult to identify in protein sequences from the UniRef database. This targeted masking mimics real-world sequencing limitations. We then modify and finetune a ProtBert derived transformer-based model, for a new downstream task predicting these masked residues, providing an approximation of the complete sequence. Evaluating on three bacterial Escherichia species, we achieve per-amino-acid accuracy up to 90.5% when only four amino acids ([KCYM]) are known. Structural assessment using AlphaFold and TM-score validates the biological relevance of our predictions. The model also demonstrates potential for evolutionary analysis through cross-species performance. This integration of simulated experimental constraints with computational predictions offers a promising avenue for enhancing protein sequence analysis, potentially accelerating advancements in proteomics and structural biology by providing a probabilistic reconstruction of the complete protein sequence from limited experimental data.

Multimodal protein language models deliver strong performance on mutation-effect prediction, but training such models from scratch demands substantial computational resources. In this paper, we propose a fine-tuning framework called InstructPLM-mu and try to answer a question: Can multimodal fine-tuning of a pretrained, sequence-only protein language model match the performance of models trained end-to-end? Surprisingly, our experiments show that fine-tuning ESM2 with structural inputs can reach performance comparable to ESM3. To understand how this is achieved, we systematically compare three different feature-fusion designs and fine-tuning recipes. Our results reveal that both the fusion method and the tuning strategy strongly affect final accuracy, indicating that the fine-tuning process is not trivial. We hope this work offers practical guidance for injecting structure into pretrained protein language models and motivates further research on better fusion mechanisms and fine-tuning protocols.

Protein representation learning is critical for numerous biological tasks. Recently, large transformer-based protein language models (pLMs) pretrained on large scale protein sequences have demonstrated significant success in sequence-based tasks. However, pLMs lack structural context. Conversely, graph neural networks (GNNs) designed to leverage 3D structural information have shown promising generalization in protein-related prediction tasks, but their effectiveness is often constrained by the scarcity of labeled structural data. Recognizing that sequence and structural representations are complementary perspectives of the same protein entity, we propose a multimodal bidirectional hierarchical fusion framework to effectively merge these modalities. Our framework employs attention and gating mechanisms to enable effective interaction between pLMs-generated sequential representations and GNN-extracted structural features, improving information exchange and enhancement across layers of the neural network. This bidirectional and hierarchical (Bi-Hierarchical) fusion approach leverages the strengths of both modalities to capture richer and more comprehensive protein representations. Based on the framework, we further introduce local Bi-Hierarchical Fusion with gating and global Bi-Hierarchical Fusion with multihead self-attention approaches. Our method demonstrates consistent improvements over strong baselines and existing fusion techniques in a variety of protein representation learning benchmarks, including enzyme EC classification, model quality assessment, protein-ligand binding affinity prediction, protein-protein binding site prediction, and B cell epitopes prediction. Our method establishes a new state-of-the-art for multimodal protein representation learning, emphasizing the efficacy of Bi-Hierarchical Fusion in bridging sequence and structural modalities.

Understanding biological processes, drug development, and biotechnological advancements requires detailed analysis of protein structures and sequences, a task in protein research that is inherently complex and time-consuming when performed manually. To streamline this process, we introduce ProteinGPT, a state-of-the-art multi-modal protein chat system, that allows users to upload protein sequences and/or structures for comprehensive protein analysis and responsive inquiries. ProteinGPT seamlessly integrates protein sequence and structure encoders with linear projection layers for precise representation adaptation, coupled with a large language model (LLM) to generate accurate and contextually relevant responses. To train ProteinGPT, we construct a large-scale dataset of 132,092 proteins with annotations, and optimize the instruction-tuning process using GPT-4o. This innovative system ensures accurate alignment between the user-uploaded data and prompts, simplifying protein analysis. Experiments show that ProteinGPT can produce promising responses to proteins and their corresponding questions.

Pre-training (PT) followed by fine-tuning (FT) is an effective method for training neural networks, and has led to significant performance improvements in many domains. PT can incorporate various design choices such as task and data reweighting strategies, augmentation policies, and noise models, all of which can significantly impact the quality of representations learned. The hyperparameters introduced by these strategies therefore must be tuned appropriately. However, setting the values of these hyperparameters is challenging. Most existing methods either struggle to scale to high dimensions, are too slow and memory-intensive, or cannot be directly applied to the two-stage PT and FT learning process. In this work, we propose an efficient, gradient-based algorithm to meta-learn PT hyperparameters. We formalize the PT hyperparameter optimization problem and propose a novel method to obtain PT hyperparameter gradients by combining implicit differentiation and backpropagation through unrolled optimization. We demonstrate that our method improves predictive performance on two real-world domains. First, we optimize high-dimensional task weighting hyperparameters for multitask pre-training on protein-protein interaction graphs and improve AUROC by up to 3.9%. Second, we optimize a data augmentation neural network for self-supervised PT with SimCLR on electrocardiography data and improve AUROC by up to 1.9%.

Motivation: The development of novel compounds targeting proteins of interest is one of the most important tasks in the pharmaceutical industry. Deep generative models have been applied to targeted molecular design and have shown promising results. Recently, target-specific molecule generation has been viewed as a translation between the protein language and the chemical language. However, such a model is limited by the availability of interacting protein-ligand pairs. On the other hand, large amounts of unlabeled protein sequences and chemical compounds are available and have been used to train language models that learn useful representations. In this study, we propose exploiting pretrained biochemical language models to initialize (i.e. warm start) targeted molecule generation models. We investigate two warm start strategies: (i) a one-stage strategy where the initialized model is trained on targeted molecule generation (ii) a two-stage strategy containing a pre-finetuning on molecular generation followed by target specific training. We also compare two decoding strategies to generate compounds: beam search and sampling. Results: The results show that the warm-started models perform better than a baseline model trained from scratch. The two proposed warm-start strategies achieve similar results to each other with respect to widely used metrics from benchmarks. However, docking evaluation of the generated compounds for a number of novel proteins suggests that the one-stage strategy generalizes better than the two-stage strategy. Additionally, we observe that beam search outperforms sampling in both docking evaluation and benchmark metrics for assessing compound quality. Availability and implementation: The source code is available at https://github.com/boun-tabi/biochemical-lms-for-drug-design and the materials are archived in Zenodo at https://doi.org/10.5281/zenodo.6832145

While decoder-only large language models (LLMs) have shown impressive results, encoder-decoder models are still widely adopted in real-world applications for their inference efficiency and richer encoder representation. In this paper, we study a novel problem: adapting pretrained decoder-only LLMs to encoder-decoder, with the goal of leveraging the strengths of both approaches to achieve a more favorable quality-efficiency trade-off. We argue that adaptation not only enables inheriting the capability of decoder-only LLMs but also reduces the demand for computation compared to pretraining from scratch. We rigorously explore different pretraining objectives and parameter initialization/optimization techniques. Through extensive experiments based on Gemma 2 (2B and 9B) and a suite of newly pretrained mT5-sized models (up to 1.6B), we demonstrate the effectiveness of adaptation and the advantage of encoder-decoder LLMs. Under similar inference budget, encoder-decoder LLMs achieve comparable (often better) pretraining performance but substantially better finetuning performance than their decoder-only counterpart. For example, Gemma 2B-2B outperforms Gemma 2B by sim7\% after instruction tuning. Encoder-decoder adaptation also allows for flexible combination of different-sized models, where Gemma 9B-2B significantly surpasses Gemma 2B-2B by >3\%. The adapted encoder representation also yields better results on SuperGLUE. We will release our checkpoints to facilitate future research.

Innovations like protein diffusion have enabled significant progress in de novo protein design, which is a vital topic in life science. These methods typically depend on protein structure encoders to model residue backbone frames, where atoms do not exist. Most prior encoders rely on atom-wise features, such as angles and distances between atoms, which are not available in this context. Thus far, only several simple encoders, such as IPA, have been proposed for this scenario, exposing the frame modeling as a bottleneck. In this work, we proffer the Vector Field Network (VFN), which enables network layers to perform learnable vector computations between coordinates of frame-anchored virtual atoms, thus achieving a higher capability for modeling frames. The vector computation operates in a manner similar to a linear layer, with each input channel receiving 3D virtual atom coordinates instead of scalar values. The multiple feature vectors output by the vector computation are then used to update the residue representations and virtual atom coordinates via attention aggregation. Remarkably, VFN also excels in modeling both frames and atoms, as the real atoms can be treated as the virtual atoms for modeling, positioning VFN as a potential universal encoder. In protein diffusion (frame modeling), VFN exhibits an impressive performance advantage over IPA, excelling in terms of both designability (67.04% vs. 53.58%) and diversity (66.54% vs. 51.98%). In inverse folding (frame and atom modeling), VFN outperforms the previous SoTA model, PiFold (54.7% vs. 51.66%), on sequence recovery rate. We also propose a method of equipping VFN with the ESM model, which significantly surpasses the previous ESM-based SoTA (62.67% vs. 55.65%), LM-Design, by a substantial margin.

We are now witnessing significant progress of deep learning methods in a variety of tasks (or datasets) of proteins. However, there is a lack of a standard benchmark to evaluate the performance of different methods, which hinders the progress of deep learning in this field. In this paper, we propose such a benchmark called PEER, a comprehensive and multi-task benchmark for Protein sEquence undERstanding. PEER provides a set of diverse protein understanding tasks including protein function prediction, protein localization prediction, protein structure prediction, protein-protein interaction prediction, and protein-ligand interaction prediction. We evaluate different types of sequence-based methods for each task including traditional feature engineering approaches, different sequence encoding methods as well as large-scale pre-trained protein language models. In addition, we also investigate the performance of these methods under the multi-task learning setting. Experimental results show that large-scale pre-trained protein language models achieve the best performance for most individual tasks, and jointly training multiple tasks further boosts the performance. The datasets and source codes of this benchmark are all available at https://github.com/DeepGraphLearning/PEER_Benchmark

Large-scale pre-training methodologies for chemical language models represent a breakthrough in cheminformatics. These methods excel in tasks such as property prediction and molecule generation by learning contextualized representations of input tokens through self-supervised learning on large unlabeled corpora. Typically, this involves pre-training on unlabeled data followed by fine-tuning on specific tasks, reducing dependence on annotated datasets and broadening chemical language representation understanding. This paper introduces a large encoder-decoder chemical foundation models pre-trained on a curated dataset of 91 million SMILES samples sourced from PubChem, which is equivalent to 4 billion of molecular tokens. The proposed foundation model supports different complex tasks, including quantum property prediction, and offer flexibility with two main variants (289M and 8times289M). Our experiments across multiple benchmark datasets validate the capacity of the proposed model in providing state-of-the-art results for different tasks. We also provide a preliminary assessment of the compositionality of the embedding space as a prerequisite for the reasoning tasks. We demonstrate that the produced latent space is separable compared to the state-of-the-art with few-shot learning capabilities.

The ability to accurately model the fitness landscape of protein sequences is critical to a wide range of applications, from quantifying the effects of human variants on disease likelihood, to predicting immune-escape mutations in viruses and designing novel biotherapeutic proteins. Deep generative models of protein sequences trained on multiple sequence alignments have been the most successful approaches so far to address these tasks. The performance of these methods is however contingent on the availability of sufficiently deep and diverse alignments for reliable training. Their potential scope is thus limited by the fact many protein families are hard, if not impossible, to align. Large language models trained on massive quantities of non-aligned protein sequences from diverse families address these problems and show potential to eventually bridge the performance gap. We introduce Tranception, a novel transformer architecture leveraging autoregressive predictions and retrieval of homologous sequences at inference to achieve state-of-the-art fitness prediction performance. Given its markedly higher performance on multiple mutants, robustness to shallow alignments and ability to score indels, our approach offers significant gain of scope over existing approaches. To enable more rigorous model testing across a broader range of protein families, we develop ProteinGym -- an extensive set of multiplexed assays of variant effects, substantially increasing both the number and diversity of assays compared to existing benchmarks.

Pre-trained large language models demonstrate potential in extracting information from DNA sequences, yet adapting to a variety of tasks and data modalities remains a challenge. To address this, we propose DNAGPT, a generalized DNA pre-training model trained on over 200 billion base pairs from all mammals. By enhancing the classic GPT model with a binary classification task (DNA sequence order), a numerical regression task (guanine-cytosine content prediction), and a comprehensive token language, DNAGPT can handle versatile DNA analysis tasks while processing both sequence and numerical data. Our evaluation of genomic signal and region recognition, mRNA abundance regression, and artificial genomes generation tasks demonstrates DNAGPT's superior performance compared to existing models designed for specific downstream tasks, benefiting from pre-training using the newly designed model structure.

Pretrained language models such as Bidirectional Encoder Representations from Transformers (BERT) have achieved state-of-the-art performance in natural language processing (NLP) tasks. Recently, BERT has been adapted to the biomedical domain. Despite the effectiveness, these models have hundreds of millions of parameters and are computationally expensive when applied to large-scale NLP applications. We hypothesized that the number of parameters of the original BERT can be dramatically reduced with minor impact on performance. In this study, we present Bioformer, a compact BERT model for biomedical text mining. We pretrained two Bioformer models (named Bioformer8L and Bioformer16L) which reduced the model size by 60% compared to BERTBase. Bioformer uses a biomedical vocabulary and was pre-trained from scratch on PubMed abstracts and PubMed Central full-text articles. We thoroughly evaluated the performance of Bioformer as well as existing biomedical BERT models including BioBERT and PubMedBERT on 15 benchmark datasets of four different biomedical NLP tasks: named entity recognition, relation extraction, question answering and document classification. The results show that with 60% fewer parameters, Bioformer16L is only 0.1% less accurate than PubMedBERT while Bioformer8L is 0.9% less accurate than PubMedBERT. Both Bioformer16L and Bioformer8L outperformed BioBERTBase-v1.1. In addition, Bioformer16L and Bioformer8L are 2-3 fold as fast as PubMedBERT/BioBERTBase-v1.1. Bioformer has been successfully deployed to PubTator Central providing gene annotations over 35 million PubMed abstracts and 5 million PubMed Central full-text articles. We make Bioformer publicly available via https://github.com/WGLab/bioformer, including pre-trained models, datasets, and instructions for downstream use.

We investigate the use of randomly generated data for the sake of pre-training a model. We justify this approach theoretically from the perspective of algorithmic complexity, building on recent research that shows that sequence models can be trained to approximate Solomonoff induction. We derive similar, but complementary theoretical results. We show empirically that synthetically generated data can be used to pre-train a model before the data is seen. We replicate earlier results that models trained this way show zero-shot in-context learning across a variety of datasets, and that this performance improves with scale. We extend earlier results to real-world data, and show that finetuning a model after pre-training offers faster convergence and better generalization.

Self-supervised training of language models (LMs) has seen great success for protein sequences in learning meaningful representations and for generative drug design. Most protein LMs are based on the Transformer architecture trained on individual proteins with short context lengths. Such protein LMs cannot extrapolate to longer proteins and protein complexes well. They also fail to account for the underlying biological mechanisms carried out by biomolecular interactions and dynamics i.e., proteins often interact with other proteins, molecules, and pathways in complex biological systems. In this work, we propose LC-PLM based on an alternative protein LM architecture, BiMamba-S, built off selective structured state-space models, to learn high-quality universal protein representations at the amino acid token level using masked language modeling. We also introduce its graph-contextual variant, LC-PLM-G, which contextualizes protein-protein interaction (PPI) graphs for a second stage of training. LC-PLM demonstrates favorable neural scaling laws, better length extrapolation capability, and a 7% to 34% improvement on protein downstream tasks than Transformer-based ESM-2. LC-PLM-G further trained within the context of PPI graphs shows promising results on protein structure and function prediction tasks. Our study demonstrates the benefit of increasing the context size with computationally efficient LM architecture (e.g. structured state space models) in learning universal protein representations and incorporating molecular interaction context contained in biological graphs.

Large pretrained models such as GPT-3 have had tremendous impact on modern natural language processing by leveraging self-supervised learning to learn salient representations that can be used to readily finetune on a wide variety of downstream tasks. We investigate the possibility of transferring such advances to molecular machine learning by building a chemical foundation model, ChemBERTa-2, using the language of SMILES. While labeled data for molecular prediction tasks is typically scarce, libraries of SMILES strings are readily available. In this work, we build upon ChemBERTa by optimizing the pretraining process. We compare multi-task and self-supervised pretraining by varying hyperparameters and pretraining dataset size, up to 77M compounds from PubChem. To our knowledge, the 77M set constitutes one of the largest datasets used for molecular pretraining to date. We find that with these pretraining improvements, we are competitive with existing state-of-the-art architectures on the MoleculeNet benchmark suite. We analyze the degree to which improvements in pretraining translate to improvement on downstream tasks.

We introduce ReALLM, a novel approach for compression and memory-efficient adaptation of pre-trained language models that encompasses most of the post-training quantization and fine-tuning methods for a budget of <4 bits. Pre-trained matrices are decomposed into a high-precision low-rank component and a vector-quantized latent representation (using an autoencoder). During the fine-tuning step, only the low-rank components are updated. Our results show that pre-trained matrices exhibit different patterns. ReALLM adapts the shape of the encoder (small/large embedding, high/low bit VQ, etc.) to each matrix. ReALLM proposes to represent each matrix with a small embedding on b bits and a neural decoder model D_phi with its weights on b_phi bits. The decompression of a matrix requires only one embedding and a single forward pass with the decoder. Our weight-only quantization algorithm yields the best results on language generation tasks (C4 and WikiText-2) for a budget of 3 bits without any training. With a budget of 2 bits, ReALLM achieves state-of-the art performance after fine-tuning on a small calibration dataset.

Deep neural networks perform well on classification tasks where data streams are i.i.d. and labeled data is abundant. Challenges emerge with non-stationary training data streams such as continual learning. One powerful approach that has addressed this challenge involves pre-training of large encoders on volumes of readily available data, followed by task-specific tuning. Given a new task, however, updating the weights of these encoders is challenging as a large number of weights needs to be fine-tuned, and as a result, they forget information about the previous tasks. In the present work, we propose a model architecture to address this issue, building upon a discrete bottleneck containing pairs of separate and learnable key-value codes. Our paradigm will be to encode; process the representation via a discrete bottleneck; and decode. Here, the input is fed to the pre-trained encoder, the output of the encoder is used to select the nearest keys, and the corresponding values are fed to the decoder to solve the current task. The model can only fetch and re-use a sparse number of these key-value pairs during inference, enabling localized and context-dependent model updates. We theoretically investigate the ability of the discrete key-value bottleneck to minimize the effect of learning under distribution shifts and show that it reduces the complexity of the hypothesis class. We empirically verify the proposed method under challenging class-incremental learning scenarios and show that the proposed model - without any task boundaries - reduces catastrophic forgetting across a wide variety of pre-trained models, outperforming relevant baselines on this task.

Sequence-to-sequence (seq2seq) learning is a popular fashion for large-scale pretraining language models. However, the prior seq2seq pretraining models generally focus on reconstructive objectives on the decoder side and neglect the effect of encoder-side supervision, which we argue may lead to sub-optimal performance. To verify our hypothesis, we first empirically study the functionalities of the encoder and decoder in seq2seq pretrained language models, and find that the encoder takes an important but under-exploitation role than the decoder regarding the downstream performance and neuron activation. Therefore, we propose an encoding-enhanced seq2seq pretraining strategy, namely E2S2, which improves the seq2seq models via integrating more efficient self-supervised information into the encoders. Specifically, E2S2 adopts two self-supervised objectives on the encoder side from two aspects: 1) locally denoising the corrupted sentence (denoising objective); and 2) globally learning better sentence representations (contrastive objective). With the help of both objectives, the encoder can effectively distinguish the noise tokens and capture high-level (i.e. syntactic and semantic) knowledge, thus strengthening the ability of seq2seq model to accurately achieve the conditional generation. On a large diversity of downstream natural language understanding and generation tasks, E2S2 dominantly improves the performance of its powerful backbone models, e.g. BART and T5. For example, upon BART backbone, we achieve +1.1% averaged gain on the general language understanding evaluation (GLUE) benchmark and +1.75% F_0.5 score improvement on CoNLL2014 dataset. We also provide in-depth analyses to show the improvement stems from better linguistic representation. We hope that our work will foster future self-supervision research on seq2seq language model pretraining.

In this paper, we present a simple and efficient GEC sequence tagger using a Transformer encoder. Our system is pre-trained on synthetic data and then fine-tuned in two stages: first on errorful corpora, and second on a combination of errorful and error-free parallel corpora. We design custom token-level transformations to map input tokens to target corrections. Our best single-model/ensemble GEC tagger achieves an F_{0.5} of 65.3/66.5 on CoNLL-2014 (test) and F_{0.5} of 72.4/73.6 on BEA-2019 (test). Its inference speed is up to 10 times as fast as a Transformer-based seq2seq GEC system. The code and trained models are publicly available.

Learning code representations has been the core prerequisite of many software engineering tasks such as code clone detection and code generation. State-of-the-art program representation techniques mainly utilize pre-trained language models (PLMs) such as CodeBERT. A Transformer encoder is firstly pre-trained on a large-scale code corpus to acquire general knowledge about source code. The pre-trained model is then fine-tuned on specific tasks using an amount of labeled data. However, gathering training samples for the downstream tasks can be prohibitively expensive and impractical for domain-specific languages or project-specific tasks. Besides, pre-training and downstream tasks are usually heterogeneous, which makes it difficult to fully explore the knowledge learned during pre-training. In this paper, we propose Zecoler, a zero-shot approach for learning code representations. Zecoler is built upon a pre-trained programming language model. In order to elicit knowledge from the PLMs efficiently, Zecoler casts the downstream tasks to the same form of pre-training objectives by inserting train-able prompts into the original input. These prompts can guide PLMs on how to generate better results. Subsequently, we employ the prompt tuning technique to search for the optimal prompts for PLMs automatically. This enables the representation model to efficiently fit the downstream tasks through fine-tuning on the dataset in source language domain and then reuse the pre-trained knowledge for the target domain in a zero-shot style. We evaluate Zecoler in five code intelligence tasks including code clone detection, code search, method name prediction, code summarization, and code generation. The results show that our approach significantly outperforms baseline models under the zero-shot setting.

Encoder-decoder models have become an effective approach for sequence learning tasks like machine translation, image captioning and speech recognition, but have yet to show competitive results for handwritten text recognition. To this end, we propose an attention-based sequence-to-sequence model. It combines a convolutional neural network as a generic feature extractor with a recurrent neural network to encode both the visual information, as well as the temporal context between characters in the input image, and uses a separate recurrent neural network to decode the actual character sequence. We make experimental comparisons between various attention mechanisms and positional encodings, in order to find an appropriate alignment between the input and output sequence. The model can be trained end-to-end and the optional integration of a hybrid loss allows the encoder to retain an interpretable and usable output, if desired. We achieve competitive results on the IAM and ICFHR2016 READ data sets compared to the state-of-the-art without the use of a language model, and we significantly improve over any recent sequence-to-sequence approaches.

This paper demonstrates that language models are strong structure-based protein designers. We present LM-Design, a generic approach to reprogramming sequence-based protein language models (pLMs), that have learned massive sequential evolutionary knowledge from the universe of natural protein sequences, to acquire an immediate capability to design preferable protein sequences for given folds. We conduct a structural surgery on pLMs, where a lightweight structural adapter is implanted into pLMs and endows it with structural awareness. During inference, iterative refinement is performed to effectively optimize the generated protein sequences. Experiments show that LM-Design improves the state-of-the-art results by a large margin, leading to up to 4% to 12% accuracy gains in sequence recovery (e.g., 55.65%/56.63% on CATH 4.2/4.3 single-chain benchmarks, and >60% when designing protein complexes). We provide extensive and in-depth analyses, which verify that LM-Design can (1) indeed leverage both structural and sequential knowledge to accurately handle structurally non-deterministic regions, (2) benefit from scaling data and model size, and (3) generalize to other proteins (e.g., antibodies and de novo proteins)

This paper studies a novel pre-training technique with unpaired speech data, Speech2C, for encoder-decoder based automatic speech recognition (ASR). Within a multi-task learning framework, we introduce two pre-training tasks for the encoder-decoder network using acoustic units, i.e., pseudo codes, derived from an offline clustering model. One is to predict the pseudo codes via masked language modeling in encoder output, like HuBERT model, while the other lets the decoder learn to reconstruct pseudo codes autoregressively instead of generating textual scripts. In this way, the decoder learns to reconstruct original speech information with codes before learning to generate correct text. Comprehensive experiments on the LibriSpeech corpus show that the proposed Speech2C can relatively reduce the word error rate (WER) by 19.2% over the method without decoder pre-training, and also outperforms significantly the state-of-the-art wav2vec 2.0 and HuBERT on fine-tuning subsets of 10h and 100h. We release our code and model at https://github.com/microsoft/SpeechT5/tree/main/Speech2C.

Proteins are fundamental to biology, executing diverse functions through complex physicochemical interactions, and they hold transformative potential across medicine, materials science, and environmental applications. Protein Language Models (pLMs) aim to unlock insights from the vast space of unlabeled protein sequences by learning rich, semantic representations from primary sequences via masked language modeling. However, these models typically exhibit limited generative capacity. In this work, we introduce the Diffusion Sequence Model (DSM), a novel pLM trained with masked diffusion to enable both high-quality representation learning and generative protein design. DSM builds upon the ESM2 architecture by incorporating a masked forward diffusion process inspired by the LLaDA framework. After training, DSM is capable of generating diverse, biomimetic sequences that align with expected amino acid compositions, secondary structures, and predicted functions, even with 90\% token corruption. Furthermore, DSM's learned representations match or exceed those of similarly sized pLMs on downstream tasks. We also introduce DSM(ppi), a variant fine-tuned to generate protein binders by attending to target sequences. We demonstrate DSM(ppi)'s effectiveness on the challenging Bench-tested Binder Benchmark (BenchBB), where both DSM and DSM(ppi) produce candidates with superior predicted binding affinity compared to known binders. Our results establish masked diffusion as a powerful paradigm for unifying protein representation and generation in a single framework.

The use of deep pre-trained bidirectional transformers has led to remarkable progress in a number of applications (Devlin et al., 2018). For tasks that make pairwise comparisons between sequences, matching a given input with a corresponding label, two approaches are common: Cross-encoders performing full self-attention over the pair and Bi-encoders encoding the pair separately. The former often performs better, but is too slow for practical use. In this work, we develop a new transformer architecture, the Poly-encoder, that learns global rather than token level self-attention features. We perform a detailed comparison of all three approaches, including what pre-training and fine-tuning strategies work best. We show our models achieve state-of-the-art results on three existing tasks; that Poly-encoders are faster than Cross-encoders and more accurate than Bi-encoders; and that the best results are obtained by pre-training on large datasets similar to the downstream tasks.

We show that protein sequences can be thought of as sentences in natural language processing and can be parsed using the existing Quantum Natural Language framework into parameterized quantum circuits of reasonable qubits, which can be trained to solve various protein-related machine-learning problems. We classify proteins based on their subcellular locations, a pivotal task in bioinformatics that is key to understanding biological processes and disease mechanisms. Leveraging the quantum-enhanced processing capabilities, we demonstrate that Quantum Tensor Networks (QTN) can effectively handle the complexity and diversity of protein sequences. We present a detailed methodology that adapts QTN architectures to the nuanced requirements of protein data, supported by comprehensive experimental results. We demonstrate two distinct QTNs, inspired by classical recurrent neural networks (RNN) and convolutional neural networks (CNN), to solve the binary classification task mentioned above. Our top-performing quantum model has achieved a 94% accuracy rate, which is comparable to the performance of a classical model that uses the ESM2 protein language model embeddings. It's noteworthy that the ESM2 model is extremely large, containing 8 million parameters in its smallest configuration, whereas our best quantum model requires only around 800 parameters. We demonstrate that these hybrid models exhibit promising performance, showcasing their potential to compete with classical models of similar complexity.

In this paper, we propose a novel neural network model called RNN Encoder-Decoder that consists of two recurrent neural networks (RNN). One RNN encodes a sequence of symbols into a fixed-length vector representation, and the other decodes the representation into another sequence of symbols. The encoder and decoder of the proposed model are jointly trained to maximize the conditional probability of a target sequence given a source sequence. The performance of a statistical machine translation system is empirically found to improve by using the conditional probabilities of phrase pairs computed by the RNN Encoder-Decoder as an additional feature in the existing log-linear model. Qualitatively, we show that the proposed model learns a semantically and syntactically meaningful representation of linguistic phrases.

Pre-trained models for Natural Languages (NL) like BERT and GPT have been recently shown to transfer well to Programming Languages (PL) and largely benefit a broad set of code-related tasks. Despite their success, most current methods either rely on an encoder-only (or decoder-only) pre-training that is suboptimal for generation (resp. understanding) tasks or process the code snippet in the same way as NL, neglecting the special characteristics of PL such as token types. We present CodeT5, a unified pre-trained encoder-decoder Transformer model that better leverages the code semantics conveyed from the developer-assigned identifiers. Our model employs a unified framework to seamlessly support both code understanding and generation tasks and allows for multi-task learning. Besides, we propose a novel identifier-aware pre-training task that enables the model to distinguish which code tokens are identifiers and to recover them when they are masked. Furthermore, we propose to exploit the user-written code comments with a bimodal dual generation task for better NL-PL alignment. Comprehensive experiments show that CodeT5 significantly outperforms prior methods on understanding tasks such as code defect detection and clone detection, and generation tasks across various directions including PL-NL, NL-PL, and PL-PL. Further analysis reveals that our model can better capture semantic information from code. Our code and pre-trained models are released at https: //github.com/salesforce/CodeT5 .

In the field of antibody engineering, an essential task is to design a novel antibody whose paratopes bind to a specific antigen with correct epitopes. Understanding antibody structure and its paratope can facilitate a mechanistic understanding of its function. Therefore, antibody structure prediction from its sequence alone has always been a highly valuable problem for de novo antibody design. AlphaFold2, a breakthrough in the field of structural biology, provides a solution to predict protein structure based on protein sequences and computationally expensive coevolutionary multiple sequence alignments (MSAs). However, the computational efficiency and undesirable prediction accuracy of antibodies, especially on the complementarity-determining regions (CDRs) of antibodies limit their applications in the industrially high-throughput drug design. To learn an informative representation of antibodies, we employed a deep antibody language model (ALM) on curated sequences from the observed antibody space database via a transformer model. We also developed a novel model named xTrimoABFold to predict antibody structure from antibody sequence based on the pretrained ALM as well as efficient evoformers and structural modules. The model was trained end-to-end on the antibody structures in PDB by minimizing the ensemble loss of domain-specific focal loss on CDR and the frame-aligned point loss. xTrimoABFold outperforms AlphaFold2 and other protein language model based SOTAs, e.g., OmegaFold, HelixFold-Single, and IgFold with a large significant margin (30+\% improvement on RMSD) while performing 151 times faster than AlphaFold2. To the best of our knowledge, xTrimoABFold achieved state-of-the-art antibody structure prediction. Its improvement in both accuracy and efficiency makes it a valuable tool for de novo antibody design and could make further improvements in immuno-theory.

Transformer architectures have proven to learn useful representations for protein classification and generation tasks. However, these representations present challenges in interpretability. In this work, we demonstrate a set of methods for analyzing protein Transformer models through the lens of attention. We show that attention: (1) captures the folding structure of proteins, connecting amino acids that are far apart in the underlying sequence, but spatially close in the three-dimensional structure, (2) targets binding sites, a key functional component of proteins, and (3) focuses on progressively more complex biophysical properties with increasing layer depth. We find this behavior to be consistent across three Transformer architectures (BERT, ALBERT, XLNet) and two distinct protein datasets. We also present a three-dimensional visualization of the interaction between attention and protein structure. Code for visualization and analysis is available at https://github.com/salesforce/provis.

Massive molecular simulations of drug-target proteins have been used as a tool to understand disease mechanism and develop therapeutics. This work focuses on learning a generative neural network on a structural ensemble of a drug-target protein, e.g. SARS-CoV-2 Spike protein, obtained from computationally expensive molecular simulations. Model tasks involve characterizing the distinct structural fluctuations of the protein bound to various drug molecules, as well as efficient generation of protein conformations that can serve as an complement of a molecular simulation engine. Specifically, we present a geometric autoencoder framework to learn separate latent space encodings of the intrinsic and extrinsic geometries of the protein structure. For this purpose, the proposed Protein Geometric AutoEncoder (ProGAE) model is trained on the protein contact map and the orientation of the backbone bonds of the protein. Using ProGAE latent embeddings, we reconstruct and generate the conformational ensemble of a protein at or near the experimental resolution, while gaining better interpretability and controllability in term of protein structure generation from the learned latent space. Additionally, ProGAE models are transferable to a different state of the same protein or to a new protein of different size, where only the dense layer decoding from the latent representation needs to be retrained. Results show that our geometric learning-based method enjoys both accuracy and efficiency for generating complex structural variations, charting the path toward scalable and improved approaches for analyzing and enhancing high-cost simulations of drug-target proteins.

The binding between proteins and ligands plays a crucial role in the realm of drug discovery. Previous deep learning approaches have shown promising results over traditional computationally intensive methods, but resulting in poor generalization due to limited supervised data. In this paper, we propose to learn protein-ligand binding representation in a self-supervised learning manner. Different from existing pre-training approaches which treat proteins and ligands individually, we emphasize to discern the intricate binding patterns from fine-grained interactions. Specifically, this self-supervised learning problem is formulated as a prediction of the conclusive binding complex structure given a pocket and ligand with a Transformer based interaction module, which naturally emulates the binding process. To ensure the representation of rich binding information, we introduce two pre-training tasks, i.e.~atomic pairwise distance map prediction and mask ligand reconstruction, which comprehensively model the fine-grained interactions from both structure and feature space. Extensive experiments have demonstrated the superiority of our method across various binding tasks, including protein-ligand affinity prediction, virtual screening and protein-ligand docking.

Inverse protein folding -- the task of predicting a protein sequence from its backbone atom coordinates -- has surfaced as an important problem in the "top down", de novo design of proteins. Contemporary approaches have cast this problem as a conditional generative modelling problem, where a large generative model over protein sequences is conditioned on the backbone. While these generative models very rapidly produce promising sequences, independent draws from generative models may fail to produce sequences that reliably fold to the correct backbone. Furthermore, it is challenging to adapt pure generative approaches to other settings, e.g., when constraints exist. In this paper, we cast the problem of improving generated inverse folds as an optimization problem that we solve using recent advances in "deep" or "latent space" Bayesian optimization. Our approach consistently produces protein sequences with greatly reduced structural error to the target backbone structure as measured by TM score and RMSD while using fewer computational resources. Additionally, we demonstrate other advantages of an optimization-based approach to the problem, such as the ability to handle constraints.

The field of protein folding research has been greatly advanced by deep learning methods, with AlphaFold2 (AF2) demonstrating exceptional performance and atomic-level precision. As co-evolution is integral to protein structure prediction, AF2's accuracy is significantly influenced by the depth of multiple sequence alignment (MSA), which requires extensive exploration of a large protein database for similar sequences. However, not all protein sequences possess abundant homologous families, and consequently, AF2's performance can degrade on such queries, at times failing to produce meaningful results. To address this, we introduce a novel generative language model, MSA-Augmenter, which leverages protein-specific attention mechanisms and large-scale MSAs to generate useful, novel protein sequences not currently found in databases. These sequences supplement shallow MSAs, enhancing the accuracy of structural property predictions. Our experiments on CASP14 demonstrate that MSA-Augmenter can generate de novo sequences that retain co-evolutionary information from inferior MSAs, thereby improving protein structure prediction quality on top of strong AF2.

We discover a robust self-supervised strategy tailored towards molecular representations for generative masked language models through a series of tailored, in-depth ablations. Using this pre-training strategy, we train BARTSmiles, a BART-like model with an order of magnitude more compute than previous self-supervised molecular representations. In-depth evaluations show that BARTSmiles consistently outperforms other self-supervised representations across classification, regression, and generation tasks setting a new state-of-the-art on 11 tasks. We then quantitatively show that when applied to the molecular domain, the BART objective learns representations that implicitly encode our downstream tasks of interest. For example, by selecting seven neurons from a frozen BARTSmiles, we can obtain a model having performance within two percentage points of the full fine-tuned model on task Clintox. Lastly, we show that standard attribution interpretability methods, when applied to BARTSmiles, highlight certain substructures that chemists use to explain specific properties of molecules. The code and the pretrained model are publicly available.

While pretrained encoders have achieved success in various natural language understanding (NLU) tasks, there is a gap between these pretrained encoders and natural language generation (NLG). NLG tasks are often based on the encoder-decoder framework, where the pretrained encoders can only benefit part of it. To reduce this gap, we introduce DeltaLM, a pretrained multilingual encoder-decoder model that regards the decoder as the task layer of off-the-shelf pretrained encoders. Specifically, we augment the pretrained multilingual encoder with a decoder and pre-train it in a self-supervised way. To take advantage of both the large-scale monolingual data and bilingual data, we adopt the span corruption and translation span corruption as the pre-training tasks. Experiments show that DeltaLM outperforms various strong baselines on both natural language generation and translation tasks, including machine translation, abstractive text summarization, data-to-text, and question generation. The code and pretrained models are available at https://aka.ms/deltalm.

In this work we introduce RITA: a suite of autoregressive generative models for protein sequences, with up to 1.2 billion parameters, trained on over 280 million protein sequences belonging to the UniRef-100 database. Such generative models hold the promise of greatly accelerating protein design. We conduct the first systematic study of how capabilities evolve with model size for autoregressive transformers in the protein domain: we evaluate RITA models in next amino acid prediction, zero-shot fitness, and enzyme function prediction, showing benefits from increased scale. We release the RITA models openly, to the benefit of the research community.

As opposed to scaling-up protein language models (PLMs), we seek improving performance via protein-specific optimization. Although the proportionality between the language model size and the richness of its learned representations is validated, we prioritize accessibility and pursue a path of data-efficient, cost-reduced, and knowledge-guided optimization. Through over twenty experiments ranging from masking, architecture, and pre-training data, we derive insights from protein-specific experimentation into building a model that interprets the language of life, optimally. We present Ankh, the first general-purpose PLM trained on Google's TPU-v4 surpassing the state-of-the-art performance with fewer parameters (<10% for pre-training, <7% for inference, and <30% for the embedding dimension). We provide a representative range of structure and function benchmarks where Ankh excels. We further provide a protein variant generation analysis on High-N and One-N input data scales where Ankh succeeds in learning protein evolutionary conservation-mutation trends and introducing functional diversity while retaining key structural-functional characteristics. We dedicate our work to promoting accessibility to research innovation via attainable resources.

We introduceGraphGPT, a novel self-supervised generative pre-trained model for graph learning based on the Graph Eulerian Transformer (GET). First, we propose GET, which combines a standard transformer encoder or decoder architecture with an innovative graph-to-sequence transformation method. This method converts graphs or sampled subgraphs into sequences of tokens representing nodes, edges, and attributes in a reversible manner using Eulerian paths. We pre-train GET using either of the two self-supervised tasks: next-token prediction (NTP) and scheduled masked-token prediction (SMTP). The pre-trained model is then fine-tuned for downstream tasks such as graph-, edge-, and node-level prediction. Despite its simplicity, GraphGPT achieves performance comparable to or surpassing state-of-the-art methods on multiple large-scale Open Graph Benchmark (OGB) datasets. It demonstrates exceptional results on the molecular property prediction dataset PCQM4Mv2 and the protein-protein interaction dataset ogbl-ppa. Notably, generative pre-training enables scaling GraphGPT to 2 billion parameters while maintaining performance gains - a breakthrough that overcomes the scalability limitations of traditional Graph Neural Networks (GNNs) and prior graph transformers (GTs). To advance research in graph foundation models and facilitate scientific discovery in chemistry, materials science, and related fields, we will release the source code (https://github.com/alibaba/graph-gpt) and pre-trained checkpoints.

Language model based pre-trained models such as BERT have provided significant gains across different NLP tasks. In this paper, we study different types of transformer based pre-trained models such as auto-regressive models (GPT-2), auto-encoder models (BERT), and seq2seq models (BART) for conditional data augmentation. We show that prepending the class labels to text sequences provides a simple yet effective way to condition the pre-trained models for data augmentation. Additionally, on three classification benchmarks, pre-trained Seq2Seq model outperforms other data augmentation methods in a low-resource setting. Further, we explore how different pre-trained model based data augmentation differs in-terms of data diversity, and how well such methods preserve the class-label information.

Recent advancements in specialized large-scale architectures for training image and language have profoundly impacted the field of computer vision and natural language processing (NLP). Language models, such as the recent ChatGPT and GPT4 have demonstrated exceptional capabilities in processing, translating, and generating human languages. These breakthroughs have also been reflected in protein research, leading to the rapid development of numerous new methods in a short time, with unprecedented performance. Language models, in particular, have seen widespread use in protein research, as they have been utilized to embed proteins, generate novel ones, and predict tertiary structures. In this book chapter, we provide an overview of the use of protein generative models, reviewing 1) language models for the design of novel artificial proteins, 2) works that use non-Transformer architectures, and 3) applications in directed evolution approaches.

Using pre-trained large language models (LLMs) as the backbone for time series prediction has recently gained significant research interest. However, the effectiveness of LLM backbones in this domain remains a topic of debate. Based on thorough empirical analyses, we observe that training and testing LLM-based models on small datasets often leads to the Encoder and Decoder becoming overly adapted to the dataset, thereby obscuring the true predictive capabilities of the LLM backbone. To investigate the genuine potential of LLMs in time series prediction, we introduce three pre-training models with identical architectures but different pre-training strategies. Thereby, large-scale pre-training allows us to create unbiased Encoder and Decoder components tailored to the LLM backbone. Through controlled experiments, we evaluate the zero-shot and few-shot prediction performance of the LLM, offering insights into its capabilities. Extensive experiments reveal that although the LLM backbone demonstrates some promise, its forecasting performance is limited. Our source code is publicly available in the anonymous repository: https://anonymous.4open.science/r/LLM4TS-0B5C.

BERT (Bidirectional Encoder Representations from Transformers) has revolutionized the field of natural language processing through its exceptional performance on numerous tasks. Yet, the majority of researchers have mainly concentrated on enhancements related to the model structure, such as relative position embedding and more efficient attention mechanisms. Others have delved into pretraining tricks associated with Masked Language Modeling, including whole word masking. DeBERTa introduced an enhanced decoder adapted for BERT's encoder model for pretraining, proving to be highly effective. We argue that the design and research around enhanced masked language modeling decoders have been underappreciated. In this paper, we propose several designs of enhanced decoders and introduce DrBERT (Decoder-refined BERT), a novel method for modeling training. Typically, a pretrained BERT model is fine-tuned for specific Natural Language Understanding (NLU) tasks. In our approach, we utilize the original BERT model as the encoder, making only changes to the decoder without altering the encoder. This approach does not necessitate extensive modifications to the model's architecture and can be seamlessly integrated into existing fine-tuning pipelines and services, offering an efficient and effective enhancement strategy. Compared to other methods, while we also incur a moderate training cost for the decoder during the pretraining process, our approach does not introduce additional training costs during the fine-tuning phase. We test multiple enhanced decoder structures after pretraining and evaluate their performance on the GLUE benchmark. Our results demonstrate that DrBERT, having only undergone subtle refinements to the model structure during pretraining, significantly enhances model performance without escalating the inference time and serving budget.

Molecular pretrained representations (MPR) has emerged as a powerful approach for addressing the challenge of limited supervised data in applications such as drug discovery and material design. While early MPR methods relied on 1D sequences and 2D graphs, recent advancements have incorporated 3D conformational information to capture rich atomic interactions. However, these prior models treat molecules merely as discrete atom sets, overlooking the space surrounding them. We argue from a physical perspective that only modeling these discrete points is insufficient. We first present a simple yet insightful observation: naively adding randomly sampled virtual points beyond atoms can surprisingly enhance MPR performance. In light of this, we propose a principled framework that incorporates the entire 3D space spanned by molecules. We implement the framework via a novel Transformer-based architecture, dubbed SpaceFormer, with three key components: (1) grid-based space discretization; (2) grid sampling/merging; and (3) efficient 3D positional encoding. Extensive experiments show that SpaceFormer significantly outperforms previous 3D MPR models across various downstream tasks with limited data, validating the benefit of leveraging the additional 3D space beyond atoms in MPR models.

Pre-training Transformers has shown promising results on open-domain and domain-specific downstream tasks. However, state-of-the-art Transformers require an unreasonably large amount of pre-training data and compute. In this paper, we propose FPDM (Fast Pre-training Technique using Document Level Metadata), a novel, compute-efficient framework that utilizes Document metadata and Domain-Specific Taxonomy as supervision signals to pre-train transformer encoder on a domain-specific corpus. The main innovation is that during domain-specific pretraining, an open-domain encoder is continually pre-trained using sentence-level embeddings as inputs (to accommodate long documents), however, fine-tuning is done with token-level embeddings as inputs to this encoder. We show that FPDM outperforms several transformer-based baselines in terms of character-level F1 scores and other automated metrics in the Customer Support, Scientific, and Legal Domains, and shows a negligible drop in performance on open-domain benchmarks. Importantly, the novel use of document-level supervision along with sentence-level embedding input for pre-training reduces pre-training compute by around 1,000, 4,500, and 500 times compared to MLM and/or NSP in Customer Support, Scientific, and Legal Domains, respectively. Code and datasets are available at https://bit.ly/FPDMCode.

Protein language models (PLMs) encode rich biological information, yet their internal neuron representations are poorly understood. We introduce the first automated framework for labeling every neuron in a PLM with biologically grounded natural language descriptions. Unlike prior approaches relying on sparse autoencoders or manual annotation, our method scales to hundreds of thousands of neurons, revealing individual neurons are selectively sensitive to diverse biochemical and structural properties. We then develop a novel neuron activation-guided steering method to generate proteins with desired traits, enabling convergence to target biochemical properties like molecular weight and instability index as well as secondary and tertiary structural motifs, including alpha helices and canonical Zinc Fingers. We finally show that analysis of labeled neurons in different model sizes reveals PLM scaling laws and a structured neuron space distribution.

Large language models (LLMs) have demonstrated significant success in natural language processing (NLP) tasks and have shown promising results in other domains such as protein sequence generation. However, there remain salient differences between LLMs used for NLP, which effectively handle multiple tasks and are available in small sizes, and protein language models that are often specialized for specific tasks and only exist in larger sizes. In this work, we introduce two small protein language models, based on Llama-3-8B and Phi-3-mini, that are capable of both uncontrollable and controllable protein generation. For the uncontrollable generation task, our best model achieves an average pLDDT score of 69.75, demonstrating robust performance in generating viable protein structures. For the controllable generation task, in which the model generates proteins according to properties specified in the prompt, we achieve a remarkable average TM-Score of 0.84, indicating high structural similarity to target proteins. We chose 10 properties, including six classes of enzymes, to extend the capabilities of prior protein language models. Our approach utilizes the Low-Rank Adaptor (LoRA) technique, reducing trainable parameters to just 4% of the original model size, lowering computational requirements. By using a subset of the UniRef50 dataset and small models, we reduced the overall training time by 70% without compromising performance. Notably, Phi-3-mini reduced trainable parameters by 60%, decreasing training cost by 30% compared to Llama 3. Consequently, Phi-3 achieved a comparable TM-Score of 0.81, demonstrating that smaller models can match the performance of larger ones, like Llama 3. We also demonstrate the deployment of our models on the energy efficient ET-SoC-1 chip, significantly improving the TPS/W by a factor of 3.

Current AI-assisted protein design mainly utilizes protein sequential and structural information. Meanwhile, there exists tremendous knowledge curated by humans in the text format describing proteins' high-level properties. Yet, whether the incorporation of such text data can help protein design tasks has not been explored. To bridge this gap, we propose ProteinDT, a multi-modal framework that leverages textual descriptions for protein design. ProteinDT consists of three subsequent steps: ProteinCLAP that aligns the representation of two modalities, a facilitator that generates the protein representation from the text modality, and a decoder that generates the protein sequences from the representation. To train ProteinDT, we construct a large dataset, SwissProtCLAP, with 441K text and protein pairs. We empirically verify the effectiveness of ProteinDT from three aspects: (1) consistently superior performance on four out of six protein property prediction benchmarks; (2) over 90% accuracy for text-guided protein generation; and (3) promising results for zero-shot text-guided protein editing.

Scene text recognition (STR) pre-training methods have achieved remarkable progress, primarily relying on synthetic datasets. However, the domain gap between synthetic and real images poses a challenge in acquiring feature representations that align well with images on real scenes, thereby limiting the performance of these methods. We note that vision-language models like CLIP, pre-trained on extensive real image-text pairs, effectively align images and text in a unified embedding space, suggesting the potential to derive the representations of real images from text alone. Building upon this premise, we introduce a novel method named Decoder Pre-training with only text for STR (DPTR). DPTR treats text embeddings produced by the CLIP text encoder as pseudo visual embeddings and uses them to pre-train the decoder. An Offline Randomized Perturbation (ORP) strategy is introduced. It enriches the diversity of text embeddings by incorporating natural image embeddings extracted from the CLIP image encoder, effectively directing the decoder to acquire the potential representations of real images. In addition, we introduce a Feature Merge Unit (FMU) that guides the extracted visual embeddings focusing on the character foreground within the text image, thereby enabling the pre-trained decoder to work more efficiently and accurately. Extensive experiments across various STR decoders and language recognition tasks underscore the broad applicability and remarkable performance of DPTR, providing a novel insight for STR pre-training. Code is available at https://github.com/Topdu/OpenOCR

Despite the extensive success of pretrained language models as encoders for building NLP systems, they haven't seen prominence as decoders for sequence generation tasks. We explore the question of whether these models can be adapted to be used as universal decoders. To be considered "universal," a decoder must have an implicit representation for any target sentence s, such that it can recover that sentence exactly when conditioned on its representation. For large transformer-based language models trained on vast amounts of English text, we investigate whether such representations can be easily discovered using standard optimization methods. We present and compare three representation injection techniques for transformer-based models and three accompanying methods which map sentences to and from this representation space. Experiments show that not only do representations exist for sentences from a variety of genres. More importantly, without needing complex optimization algorithms, our methods recover these sentences almost perfectly without fine-tuning the underlying language model at all.

The rapid expansion of genomic sequence data calls for new methods to achieve robust sequence representations. Existing techniques often neglect intricate structural details, emphasizing mainly contextual information. To address this, we developed k-mer embeddings that merge contextual and structural string information by enhancing De Bruijn graphs with structural similarity connections. Subsequently, we crafted a self-supervised method based on Contrastive Learning that employs a heterogeneous Graph Convolutional Network encoder and constructs positive pairs based on node similarities. Our embeddings consistently outperform prior techniques for Edit Distance Approximation and Closest String Retrieval tasks.

Recently, the advances in vision-language models, including contrastive pretraining and instruction tuning, have greatly pushed the frontier of multimodal AI. However, owing to the large-scale and hence expensive pretraining, the efficiency concern has discouraged researchers from attempting to pretrain a vision language model from scratch. In this work, we propose Dynamic patch Reduction via Interpretable Pooling (DRIP), which adapts to the input images and dynamically merges tokens in the deeper layers of a visual encoder. Our results on both ImageNet training from scratch and CLIP contrastive pretraining demonstrate a significant GFLOP reduction while maintaining comparable classification/zero-shot performance. To further validate our proposed method, we conduct continual pretraining on a large biology dataset, extending its impact into scientific domains.

Despite significant progress of generative models in the natural sciences, their controllability remains challenging. One fundamentally missing aspect of molecular or protein generative models is an inductive bias that can reflect continuous properties of interest. To that end, we propose the Regression Transformer (RT), a novel method that abstracts regression as a conditional sequence modeling problem. This introduces a new paradigm of multitask language models which seamlessly bridge sequence regression and conditional sequence generation. We thoroughly demonstrate that, despite using a nominal-scale training objective, the RT matches or surpasses the performance of conventional regression models in property prediction tasks of small molecules, proteins and chemical reactions. Critically, priming the same model with continuous properties yields a highly competitive conditional generative model that outperforms specialized approaches in a substructure-constrained, property-driven molecule generation benchmark. Our dichotomous approach is facilitated by a novel, alternating training scheme that enables the model to decorate seed sequences by desired properties, e.g., to optimize reaction yield. In sum, the RT is the first report of a multitask model that concurrently excels at predictive and generative tasks in biochemistry. This finds particular application in property-driven, local exploration of the chemical or protein space and could pave the road toward foundation models in material design. The code to reproduce all experiments of the paper is available at: https://github.com/IBM/regression-transformer

Recent advances in natural language processing (NLP) can be largely attributed to the advent of pre-trained language models such as BERT and RoBERTa. While these models demonstrate remarkable performance on general datasets, they can struggle in specialized domains such as medicine, where unique domain-specific terminologies, domain-specific abbreviations, and varying document structures are common. This paper explores strategies for adapting these models to domain-specific requirements, primarily through continuous pre-training on domain-specific data. We pre-trained several German medical language models on 2.4B tokens derived from translated public English medical data and 3B tokens of German clinical data. The resulting models were evaluated on various German downstream tasks, including named entity recognition (NER), multi-label classification, and extractive question answering. Our results suggest that models augmented by clinical and translation-based pre-training typically outperform general domain models in medical contexts. We conclude that continuous pre-training has demonstrated the ability to match or even exceed the performance of clinical models trained from scratch. Furthermore, pre-training on clinical data or leveraging translated texts have proven to be reliable methods for domain adaptation in medical NLP tasks.

Many pre-trained language models (PLMs) exhibit suboptimal performance on mid- and low-resource languages, largely due to limited exposure to these languages during pre-training. A common strategy to address this is to introduce new tokens specific to the target languages, initialize their embeddings, and apply continual pre-training on target-language data. Among such methods, OFA (Liu et al., 2024a) proposes a similarity-based subword embedding initialization heuristic that is both effective and efficient. However, OFA restricts target-language token embeddings to be convex combinations of a fixed number of source-language embeddings, which may limit expressiveness. To overcome this limitation, we propose HYPEROFA, a hypernetwork-based approach for more adaptive token embedding initialization. The hypernetwork is trained to map from an external multilingual word vector space to the PLMs token embedding space using source-language tokens. Once trained, it can generate flexible embeddings for target-language tokens, serving as a good starting point for continual pretraining. Experiments demonstrate that HYPEROFA consistently outperforms random initialization baseline and matches or exceeds the performance of OFA in both continual pre-training convergence and downstream task performance. We make the code publicly available.

Most of the current transformer-based chemical language models are pre-trained on millions to billions of molecules. However, the improvement from such scaling in dataset size is not confidently linked to improved molecular property prediction. The aim of this study is to investigate and overcome some of the limitations of transformer models in predicting molecular properties. Specifically, we examine the impact of pre-training dataset size and diversity on the performance of transformer models and investigate the use of domain adaptation as a technique for improving model performance. First, our findings indicate that increasing pretraining dataset size beyond 400K molecules from the GuacaMol dataset does not result in a significant improvement on four ADME endpoints, namely, solubility, permeability, microsomal stability, and plasma protein binding. Second, our results demonstrate that using domain adaptation by further training the transformer model on a small set of domain-relevant molecules, i.e., a few hundred to a few thousand, using multi-task regression of physicochemical properties was sufficient to significantly improve performance for three out of the four investigated ADME endpoints (P-value < 0.001). Finally, we observe that a model pre-trained on 400K molecules and domain adopted on a few hundred/thousand molecules performs similarly (P-value > 0.05) to more complicated transformer models like MolBERT(pre-trained on 1.3M molecules) and MolFormer (pre-trained on 100M molecules). A comparison to a random forest model trained on basic physicochemical properties showed similar performance to the examined transformer models. We believe that current transformer models can be improved through further systematic analysis of pre-training and downstream data, pre-training objectives, and scaling laws, ultimately leading to better and more helpful models.

Large language models (LLMs) pretrained on vast source code have achieved prominent progress in code intelligence. However, existing code LLMs have two main limitations in terms of architecture and pretraining tasks. First, they often adopt a specific architecture (encoder-only or decoder-only) or rely on a unified encoder-decoder network for different downstream tasks. The former paradigm is limited by inflexibility in applications while in the latter, the model is treated as a single system for all tasks, leading to suboptimal performance on a subset of tasks. Secondly, they often employ a limited set of pretraining objectives which might not be relevant to some downstream tasks and hence result in substantial performance degrade. To address these limitations, we propose ``CodeT5+'', a family of encoder-decoder LLMs for code in which component modules can be flexibly combined to suit a wide range of downstream code tasks. Such flexibility is enabled by our proposed mixture of pretraining objectives to mitigate the pretrain-finetune discrepancy. These objectives cover span denoising, contrastive learning, text-code matching, and causal LM pretraining tasks, on both unimodal and bimodal multilingual code corpora. Furthermore, we propose to initialize CodeT5+ with frozen off-the-shelf LLMs without training from scratch to efficiently scale up our models, and explore instruction-tuning to align with natural language instructions. We extensively evaluate CodeT5+ on over 20 code-related benchmarks in different settings, including zero-shot, finetuning, and instruction-tuning. We observe state-of-the-art (SoTA) model performance on various code-related tasks, such as code generation and completion, math programming, and text-to-code retrieval tasks. Particularly, our instruction-tuned CodeT5+ 16B achieves new SoTA results on HumanEval code generation task against other open code LLMs.

The world of language models is going through turbulent times, better and ever larger models are coming out at an unprecedented speed. However, we argue that, especially for the scientific community, encoder models of up to 1 billion parameters are still very much needed, their primary usage being in enriching large collections of data with metadata necessary for downstream research. We investigate the best way to ensure the existence of such encoder models on the set of very closely related languages - Croatian, Serbian, Bosnian and Montenegrin, by setting up a diverse benchmark for these languages, and comparing the trained-from-scratch models with the new models constructed via additional pretraining of existing multilingual models. We show that comparable performance to dedicated from-scratch models can be obtained by additionally pretraining available multilingual models even with a limited amount of computation. We also show that neighboring languages, in our case Slovenian, can be included in the additional pretraining with little to no loss in the performance of the final model.

Recent advances in Language Models have enabled the protein modeling community with a powerful tool since protein sequences can be represented as text. Specifically, by taking advantage of Transformers, sequence-to-property prediction will be amenable without the need for explicit structural data. In this work, inspired by recent progress in Large Language Models (LLMs), we introduce PeptideBERT, a protein language model for predicting three key properties of peptides (hemolysis, solubility, and non-fouling). The PeptideBert utilizes the ProtBERT pretrained transformer model with 12 attention heads and 12 hidden layers. We then finetuned the pretrained model for the three downstream tasks. Our model has achieved state of the art (SOTA) for predicting Hemolysis, which is a task for determining peptide's potential to induce red blood cell lysis. Our PeptideBert non-fouling model also achieved remarkable accuracy in predicting peptide's capacity to resist non-specific interactions. This model, trained predominantly on shorter sequences, benefits from the dataset where negative examples are largely associated with insoluble peptides. Codes, models, and data used in this study are freely available at: https://github.com/ChakradharG/PeptideBERT

Large Language Models (LLMs), including GPT-x and LLaMA2, have achieved remarkable performance in multiple Natural Language Processing (NLP) tasks. Under the premise that protein sequences constitute the protein language, Protein Large Language Models (ProLLMs) trained on protein corpora excel at de novo protein sequence generation. However, as of now, unlike LLMs in NLP, no ProLLM is capable of multiple tasks in the Protein Language Processing (PLP) field. This prompts us to delineate the inherent limitations in current ProLLMs: (i) the lack of natural language capabilities, (ii) insufficient instruction understanding, and (iii) high training resource demands. To address these challenges, we introduce a training framework to transform any general LLM into a ProLLM capable of handling multiple PLP tasks. Specifically, our framework utilizes low-rank adaptation and employs a two-stage training approach, and it is distinguished by its universality, low overhead, and scalability. Through training under this framework, we propose the ProLLaMA model, the first known ProLLM to handle multiple PLP tasks simultaneously. Experiments show that ProLLaMA achieves state-of-the-art results in the unconditional protein sequence generation task. In the controllable protein sequence generation task, ProLLaMA can design novel proteins with desired functionalities. In the protein property prediction task, ProLLaMA achieves nearly 100\% accuracy across many categories. The latter two tasks are beyond the reach of other ProLLMs. Code is available at https://github.com/Lyu6PosHao/ProLLaMA.

Recent studies have been increasingly demonstrating that high-quality data is crucial for effective pretraining of language models. However, the precise definition of "high-quality" remains underexplored. Focusing on the code domain, we introduce Arctic-SnowCoder-1.3B, a data-efficient base code model pretrained on 555B tokens through three phases of progressively refined data: (1) general pretraining with 500B standard-quality code tokens, preprocessed through basic filtering, deduplication, and decontamination, (2) continued pretraining with 50B high-quality tokens, selected from phase one by a BERT-style quality annotator trained to distinguish good code from random data, using positive examples drawn from high-quality code files, along with instruction data from Magicoder and StarCoder2-Instruct, and (3) enhanced pretraining with 5B synthetic data created by Llama-3.1-70B using phase two data as seeds, adapting the Magicoder approach for pretraining. Despite being trained on a limited dataset, Arctic-SnowCoder achieves state-of-the-art performance on BigCodeBench, a coding benchmark focusing on practical and challenging programming tasks, compared to similarly sized models trained on no more than 1T tokens, outperforming Phi-1.5-1.3B by 36%. Across all evaluated benchmarks, Arctic-SnowCoder-1.3B beats StarCoderBase-3B pretrained on 1T tokens. Additionally, it matches the performance of leading small base code models trained on trillions of tokens. For example, Arctic-SnowCoder-1.3B surpasses StarCoder2-3B, pretrained on over 3.3T tokens, on HumanEval+, a benchmark that evaluates function-level code generation, and remains competitive on BigCodeBench. Our evaluation presents a comprehensive analysis justifying various design choices for Arctic-SnowCoder. Most importantly, we find that the key to high-quality data is its alignment with the distribution of downstream applications.

In this paper, we propose a novel pretraining-based encoder-decoder framework, which can generate the output sequence based on the input sequence in a two-stage manner. For the encoder of our model, we encode the input sequence into context representations using BERT. For the decoder, there are two stages in our model, in the first stage, we use a Transformer-based decoder to generate a draft output sequence. In the second stage, we mask each word of the draft sequence and feed it to BERT, then by combining the input sequence and the draft representation generated by BERT, we use a Transformer-based decoder to predict the refined word for each masked position. To the best of our knowledge, our approach is the first method which applies the BERT into text generation tasks. As the first step in this direction, we evaluate our proposed method on the text summarization task. Experimental results show that our model achieves new state-of-the-art on both CNN/Daily Mail and New York Times datasets.

We present a novel approach for the prediction of anticancer compound sensitivity by means of multi-modal attention-based neural networks (PaccMann). In our approach, we integrate three key pillars of drug sensitivity, namely, the molecular structure of compounds, transcriptomic profiles of cancer cells as well as prior knowledge about interactions among proteins within cells. Our models ingest a drug-cell pair consisting of SMILES encoding of a compound and the gene expression profile of a cancer cell and predicts an IC50 sensitivity value. Gene expression profiles are encoded using an attention-based encoding mechanism that assigns high weights to the most informative genes. We present and study three encoders for SMILES string of compounds: 1) bidirectional recurrent 2) convolutional 3) attention-based encoders. We compare our devised models against a baseline model that ingests engineered fingerprints to represent the molecular structure. We demonstrate that using our attention-based encoders, we can surpass the baseline model. The use of attention-based encoders enhance interpretability and enable us to identify genes, bonds and atoms that were used by the network to make a prediction.

We introduce a new neural architecture to learn the conditional probability of an output sequence with elements that are discrete tokens corresponding to positions in an input sequence. Such problems cannot be trivially addressed by existent approaches such as sequence-to-sequence and Neural Turing Machines, because the number of target classes in each step of the output depends on the length of the input, which is variable. Problems such as sorting variable sized sequences, and various combinatorial optimization problems belong to this class. Our model solves the problem of variable size output dictionaries using a recently proposed mechanism of neural attention. It differs from the previous attention attempts in that, instead of using attention to blend hidden units of an encoder to a context vector at each decoder step, it uses attention as a pointer to select a member of the input sequence as the output. We call this architecture a Pointer Net (Ptr-Net). We show Ptr-Nets can be used to learn approximate solutions to three challenging geometric problems -- finding planar convex hulls, computing Delaunay triangulations, and the planar Travelling Salesman Problem -- using training examples alone. Ptr-Nets not only improve over sequence-to-sequence with input attention, but also allow us to generalize to variable size output dictionaries. We show that the learnt models generalize beyond the maximum lengths they were trained on. We hope our results on these tasks will encourage a broader exploration of neural learning for discrete problems.

Self-supervised representation learning of biological sequence embeddings alleviates computational resource constraints on downstream tasks while circumventing expensive experimental label acquisition. However, existing methods mostly borrow directly from large language models designed for NLP, rather than with bioinformatics philosophies in mind. Recently, contrastive mutual information maximization methods have achieved state-of-the-art representations for ImageNet. In this perspective piece, we discuss how viewing evolution as natural sequence augmentation and maximizing information across phylogenetic "noisy channels" is a biologically and theoretically desirable objective for pretraining encoders. We first provide a review of current contrastive learning literature, then provide an illustrative example where we show that contrastive learning using evolutionary augmentation can be used as a representation learning objective which maximizes the mutual information between biological sequences and their conserved function, and finally outline rationale for this approach.

The rapid advancements in transformer-based language models have revolutionized natural language processing, yet understanding the internal mechanisms of these models remains a significant challenge. This paper explores the application of sparse autoencoders (SAE) to interpret the internal representations of protein language models, specifically focusing on the ESM-2 8M parameter model. By performing a statistical analysis on each latent component's relevance to distinct protein annotations, we identify potential interpretations linked to various protein characteristics, including transmembrane regions, binding sites, and specialized motifs. We then leverage these insights to guide sequence generation, shortlisting the relevant latent components that can steer the model towards desired targets such as zinc finger domains. This work contributes to the emerging field of mechanistic interpretability in biological sequence models, offering new perspectives on model steering for sequence design.

Pre-trained language models (PLMs) have become a prevalent technique in deep learning for code, utilizing a two-stage pre-training and fine-tuning procedure to acquire general knowledge about code and specialize in a variety of downstream tasks. However, the dynamic nature of software codebases poses a challenge to the effectiveness and robustness of PLMs. In particular, world-realistic scenarios potentially lead to significant differences between the distribution of the pre-training and test data, i.e., distribution shift, resulting in a degradation of the PLM's performance on downstream tasks. In this paper, we stress the need for adapting PLMs of code to software data whose distribution changes over time, a crucial problem that has been overlooked in previous works. The motivation of this work is to consider the PLM in a non-stationary environment, where fine-tuning data evolves over time according to a software evolution scenario. Specifically, we design a scenario where the model needs to learn from a stream of programs containing new, unseen APIs over time. We study two widely used PLM architectures, i.e., a GPT2 decoder and a RoBERTa encoder, on two downstream tasks, API call and API usage prediction. We demonstrate that the most commonly used fine-tuning technique from prior work is not robust enough to handle the dynamic nature of APIs, leading to the loss of previously acquired knowledge i.e., catastrophic forgetting. To address these issues, we implement five continual learning approaches, including replay-based and regularization-based methods. Our findings demonstrate that utilizing these straightforward methods effectively mitigates catastrophic forgetting in PLMs across both downstream tasks while achieving comparable or superior performance.

Proteins, as essential biomolecules, play a central role in biological processes, including metabolic reactions and DNA replication. Accurate prediction of their properties and functions is crucial in biological applications. Recent development of protein language models (pLMs) with supervised fine tuning provides a promising solution to this problem. However, the fine-tuned model is tailored for particular downstream prediction task, and achieving general-purpose protein understanding remains a challenge. In this paper, we introduce Structure-Enhanced Protein Instruction Tuning (SEPIT) framework to bridge this gap. Our approach integrates a noval structure-aware module into pLMs to inform them with structural knowledge, and then connects these enhanced pLMs to large language models (LLMs) to generate understanding of proteins. In this framework, we propose a novel two-stage instruction tuning pipeline that first establishes a basic understanding of proteins through caption-based instructions and then refines this understanding using a mixture of experts (MoEs) to learn more complex properties and functional information with the same amount of activated parameters. Moreover, we construct the largest and most comprehensive protein instruction dataset to date, which allows us to train and evaluate the general-purpose protein understanding model. Extensive experimental results on open-ended generation and closed-set answer tasks demonstrate the superior performance of SEPIT over both closed-source general LLMs and open-source LLMs trained with protein knowledge.

Recent advancements in NLP have witnessed the groundbreaking impact of pretrained models, yielding impressive outcomes across various tasks. This study seeks to extend the power of pretraining methodologies to facilitating the prediction over tables in data science, a domain traditionally overlooked, yet inherently challenging due to the plethora of table schemas intrinsic to different tasks. The primary research questions underpinning this work revolve around the establishment of a universal pretraining protocol for tables with varied structures, the generalizability and transferability of learned knowledge across tasks, the adaptation to diverse downstream applications, and the incorporation of incremental columns over time. In response to these challenges, we introduce UniTabE, a straightforward yet effective method designed to process tables in a uniform manner, devoid of constraints imposed by specific table structures. UniTabE's core concept relies on representing each basic table element with a module, termed TabUnit. This is subsequently followed by a Transformer encoder to refine the representation. Moreover, our model is designed to facilitate pretraining and finetuning through the utilization of free-form prompts. In order to implement the pretraining phase, we curated an expansive tabular dataset comprising approximately 13B samples, meticulously gathered from the Kaggle platform. This research primarily centers on classification and regression tasks involving tabular data, and conducts rigorous experimental testing and analyses to validate the effectiveness of our methodology. The experimental results demonstrate UniTabE's superior performance against several baselines across massive benchmarks. This, therefore, underscores UniTabE's potential to significantly enhance the semantic representation of tabular data, thereby marking a significant stride for tabular data analysis.

Understanding how and what pre-trained language models (PLMs) learn about language is an open challenge in natural language processing. Previous work has focused on identifying whether they capture semantic and syntactic information, and how the data or the pre-training objective affects their performance. However, to the best of our knowledge, no previous work has specifically examined how information loss in input token characters affects the performance of PLMs. In this study, we address this gap by pre-training language models using small subsets of characters from individual tokens. Surprisingly, we find that pre-training even under extreme settings, i.e. using only one character of each token, the performance retention in standard NLU benchmarks and probing tasks compared to full-token models is high. For instance, a model pre-trained only on single first characters from tokens achieves performance retention of approximately 90\% and 77\% of the full-token model in SuperGLUE and GLUE tasks, respectively.

Recently, there has been a significant upsurge of interest in leveraging large language models (LLMs) to assist scientific discovery. However, most LLMs only focus on general science, while they lack domain-specific knowledge, such as chemical molecules and amino acid sequences. To bridge these gaps, we introduce SciDFM, a mixture-of-experts LLM, which is trained from scratch and is able to conduct college-level scientific reasoning and understand molecules and amino acid sequences. We collect a large-scale training corpus containing numerous scientific papers and books from different disciplines as well as data from domain-specific databases. We further fine-tune the pre-trained model on lots of instruction data to improve performances on downstream benchmarks. From experiment results, we show that SciDFM achieves strong performance on general scientific benchmarks such as SciEval and SciQ, and it reaches a SOTA performance on domain-specific benchmarks among models of similar size. We further analyze the expert layers and show that the results of expert selection vary with data from different disciplines. To benefit the broader research community, we open-source SciDFM at https://huggingface.co/OpenDFM/SciDFM-MoE-A5.6B-v1.0.

This paper introduces WeatherFormer, a transformer encoder-based model designed to learn robust weather features from minimal observations. It addresses the challenge of modeling complex weather dynamics from small datasets, a bottleneck for many prediction tasks in agriculture, epidemiology, and climate science. WeatherFormer was pretrained on a large pretraining dataset comprised of 39 years of satellite measurements across the Americas. With a novel pretraining task and fine-tuning, WeatherFormer achieves state-of-the-art performance in county-level soybean yield prediction and influenza forecasting. Technical innovations include a unique spatiotemporal encoding that captures geographical, annual, and seasonal variations, adapting the transformer architecture to continuous weather data, and a pretraining strategy to learn representations that are robust to missing weather features. This paper for the first time demonstrates the effectiveness of pretraining large transformer encoder models for weather-dependent applications across multiple domains.

State-of-the-art language models are autoregressive and operate on subword units known as tokens. Specifically, one must encode the conditioning string into a list of tokens before passing to the language models for next-token prediction. We show that popular encoding schemes, such as maximum prefix encoding (MPE) and byte-pair-encoding (BPE), induce a sampling bias that cannot be mitigated with more training or data. To counter this universal problem, for each encoding scheme above, we propose a novel algorithm to obtain unbiased estimates from any language model trained on tokenized data. Our methods do not require finetuning the model, and the complexity, defined as the number of model runs, scales linearly with the sequence length in the case of MPE. As a result, we show that one can simulate token-free behavior from a tokenized language model. We empirically verify the correctness of our method through a Markov-chain setup, where it accurately recovers the transition probabilities, as opposed to the conventional method of directly prompting tokens into the language model.