J. Tang

Minghao Xu, Zuobai Zhang, Jiarui Lu et al.

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

Yangtian Zhang, Zuobai Zhang, Bozitao Zhong et al.

Proteins play a critical role in carrying out biological functions, and their 3D structures are essential in determining their functions. Accurately predicting the conformation of protein side-chains given their backbones is important for applications in protein structure prediction, design and protein-protein interactions. Traditional methods are computationally intensive and have limited accuracy, while existing machine learning methods treat the problem as a regression task and overlook the restrictions imposed by the constant covalent bond lengths and angles. In this work, we present DiffPack, a torsional diffusion model that learns the joint distribution of side-chain torsional angles, the only degrees of freedom in side-chain packing, by diffusing and denoising on the torsional space. To avoid issues arising from simultaneous perturbation of all four torsional angles, we propose autoregressively generating the four torsional angles from $χ_1$ to $χ_4$ and training diffusion models for each torsional angle. We evaluate the method on several benchmarks for protein side-chain packing and show that our method achieves improvements of $11.9\%$ and $13.5\%$ in angle accuracy on CASP13 and CASP14, respectively, with a significantly smaller model size ($60\times$ fewer parameters). Additionally, we show the effectiveness of our method in enhancing side-chain predictions in the AlphaFold2 model. Code is available at https://github.com/DeepGraphLearning/DiffPack.

Zuobai Zhang, Chuanrui Wang, Minghao Xu et al.

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.

Zuobai Zhang, Minghao Xu, Aurélie Lozano et al.

Self-supervised pre-training methods on proteins have recently gained attention, with most approaches focusing on either protein sequences or structures, neglecting the exploration of their joint distribution, which is crucial for a comprehensive understanding of protein functions by integrating co-evolutionary information and structural characteristics. In this work, inspired by the success of denoising diffusion models in generative tasks, we propose the DiffPreT approach to pre-train a protein encoder by sequence-structure joint diffusion modeling. DiffPreT guides the encoder to recover the native protein sequences and structures from the perturbed ones along the joint diffusion trajectory, which acquires the joint distribution of sequences and structures. Considering the essential protein conformational variations, we enhance DiffPreT by a method called Siamese Diffusion Trajectory Prediction (SiamDiff) to capture the correlation between different conformers of a protein. SiamDiff attains this goal by maximizing the mutual information between representations of diffusion trajectories of structurally-correlated conformers. We study the effectiveness of DiffPreT and SiamDiff on both atom- and residue-level structure-based protein understanding tasks. Experimental results show that the performance of DiffPreT is consistently competitive on all tasks, and SiamDiff achieves new state-of-the-art performance, considering the mean ranks on all tasks. Our implementation is available at https://github.com/DeepGraphLearning/SiamDiff.

Chuanrui Wang, Bozitao Zhong, Zuobai Zhang et al.

Structure-based protein design has attracted increasing interest, with numerous methods being introduced in recent years. However, a universally accepted method for evaluation has not been established, since the wet-lab validation can be overly time-consuming for the development of new algorithms, and the $\textit{in silico}$ validation with recovery and perplexity metrics is efficient but may not precisely reflect true foldability. To address this gap, we introduce two novel metrics: refoldability-based metric, which leverages high-accuracy protein structure prediction models as a proxy for wet lab experiments, and stability-based metric, which assesses whether models can assign high likelihoods to experimentally stable proteins. We curate datasets from high-quality CATH protein data, high-throughput $\textit{de novo}$ designed proteins, and mega-scale experimental mutagenesis experiments, and in doing so, present the $\textbf{PDB-Struct}$ benchmark that evaluates both recent and previously uncompared protein design methods. Experimental results indicate that ByProt, ProteinMPNN, and ESM-IF perform exceptionally well on our benchmark, while ESM-Design and AF-Design fall short on the refoldability metric. We also show that while some methods exhibit high sequence recovery, they do not perform as well on our new benchmark. Our proposed benchmark paves the way for a fair and comprehensive evaluation of protein design methods in the future. Code is available at https://github.com/WANG-CR/PDB-Struct.

Arian R. Jamasb, Alex Morehead, Chaitanya K. Joshi et al.

We introduce ProteinWorkshop, a comprehensive benchmark suite for representation learning on protein structures with Geometric Graph Neural Networks. We consider large-scale pre-training and downstream tasks on both experimental and predicted structures to enable the systematic evaluation of the quality of the learned structural representation and their usefulness in capturing functional relationships for downstream tasks. We find that: (1) large-scale pretraining on AlphaFold structures and auxiliary tasks consistently improve the performance of both rotation-invariant and equivariant GNNs, and (2) more expressive equivariant GNNs benefit from pretraining to a greater extent compared to invariant models. We aim to establish a common ground for the machine learning and computational biology communities to rigorously compare and advance protein structure representation learning. Our open-source codebase reduces the barrier to entry for working with large protein structure datasets by providing: (1) storage-efficient dataloaders for large-scale structural databases including AlphaFoldDB and ESM Atlas, as well as (2) utilities for constructing new tasks from the entire PDB. ProteinWorkshop is available at: github.com/a-r-j/ProteinWorkshop.

Xiangru Tang, Qiao Jin, Kunlun Zhu et al.

AI scientists powered by large language models have demonstrated substantial promise in autonomously conducting experiments and facilitating scientific discoveries across various disciplines. While their capabilities are promising, these agents also introduce novel vulnerabilities that require careful consideration for safety. However, there has been limited comprehensive exploration of these vulnerabilities. This perspective examines vulnerabilities in AI scientists, shedding light on potential risks associated with their misuse, and emphasizing the need for safety measures. We begin by providing an overview of the potential risks inherent to AI scientists, taking into account user intent, the specific scientific domain, and their potential impact on the external environment. Then, we explore the underlying causes of these vulnerabilities and provide a scoping review of the limited existing works. Based on our analysis, we propose a triadic framework involving human regulation, agent alignment, and an understanding of environmental feedback (agent regulation) to mitigate these identified risks. Furthermore, we highlight the limitations and challenges associated with safeguarding AI scientists and advocate for the development of improved models, robust benchmarks, and comprehensive regulations.

Xiaoyin Chen, Jiarui Lu, Minsu Kim et al. · mila

Reinforcement learning (RL) has proven effective for fine-tuning large language models (LLMs), significantly enhancing their reasoning abilities in domains such as mathematics and code generation. A crucial factor influencing RL fine-tuning success is the training curriculum: the order in which training problems are presented. While random curricula serve as common baselines, they remain suboptimal; manually designed curricula often rely heavily on heuristics, and online filtering methods can be computationally prohibitive. To address these limitations, we propose Self-Evolving Curriculum (SEC), an automatic curriculum learning method that learns a curriculum policy concurrently with the RL fine-tuning process. Our approach formulates curriculum selection as a non-stationary Multi-Armed Bandit problem, treating each problem category (e.g., difficulty level or problem type) as an individual arm. We leverage the absolute advantage from policy gradient methods as a proxy measure for immediate learning gain. At each training step, the curriculum policy selects categories to maximize this reward signal and is updated using the TD(0) method. Across three distinct reasoning domains: planning, inductive reasoning, and mathematics, our experiments demonstrate that SEC significantly improves models' reasoning capabilities, enabling better generalization to harder, out-of-distribution test problems. Additionally, our approach achieves better skill balance when fine-tuning simultaneously on multiple reasoning domains. These findings highlight SEC as a promising strategy for RL fine-tuning of LLMs.

Dong Chen, Ning Liu, Yichen Zhu et al.

Neural network compression techniques, such as knowledge distillation (KD) and network pruning, have received increasing attention. Recent work `Prune, then Distill' reveals that a pruned student-friendly teacher network can benefit the performance of KD. However, the conventional teacher-student pipeline, which entails cumbersome pre-training of the teacher and complicated compression steps, makes pruning with KD less efficient. In addition to compressing models, recent compression techniques also emphasize the aspect of efficiency. Early pruning demands significantly less computational cost in comparison to the conventional pruning methods as it does not require a large pre-trained model. Likewise, a special case of KD, known as self-distillation (SD), is more efficient since it requires no pre-training or student-teacher pair selection. This inspires us to collaborate early pruning with SD for efficient model compression. In this work, we propose the framework named Early Pruning with Self-Distillation (EPSD), which identifies and preserves distillable weights in early pruning for a given SD task. EPSD efficiently combines early pruning and self-distillation in a two-step process, maintaining the pruned network's trainability for compression. Instead of a simple combination of pruning and SD, EPSD enables the pruned network to favor SD by keeping more distillable weights before training to ensure better distillation of the pruned network. We demonstrated that EPSD improves the training of pruned networks, supported by visual and quantitative analyses. Our evaluation covered diverse benchmarks (CIFAR-10/100, Tiny-ImageNet, full ImageNet, CUB-200-2011, and Pascal VOC), with EPSD outperforming advanced pruning and SD techniques.

Zuobai Zhang, Jiarui Lu, Vijil Chenthamarakshan et al.

Protein function annotation is an important yet challenging task in biology. Recent deep learning advancements show significant potential for accurate function prediction by learning from protein sequences and structures. Nevertheless, these predictor-based methods often overlook the modeling of protein similarity, an idea commonly employed in traditional approaches using sequence or structure retrieval tools. To fill this gap, we first study the effect of inter-protein similarity modeling by benchmarking retriever-based methods against predictors on protein function annotation tasks. Our results show that retrievers can match or outperform predictors without large-scale pre-training. Building on these insights, we introduce a novel variational pseudo-likelihood framework, ProtIR, designed to improve function predictors by incorporating inter-protein similarity modeling. This framework iteratively refines knowledge between a function predictor and retriever, thereby combining the strengths of both predictors and retrievers. ProtIR showcases around 10% improvement over vanilla predictor-based methods. Besides, it achieves performance on par with protein language model-based methods, yet without the need for massive pre-training, highlighting the efficacy of our framework. Code will be released upon acceptance.

Zhaocheng Zhu, Chence Shi, Zuobai Zhang et al.

Machine learning has huge potential to revolutionize the field of drug discovery and is attracting increasing attention in recent years. However, lacking domain knowledge (e.g., which tasks to work on), standard benchmarks and data preprocessing pipelines are the main obstacles for machine learning researchers to work in this domain. To facilitate the progress of machine learning for drug discovery, we develop TorchDrug, a powerful and flexible machine learning platform for drug discovery built on top of PyTorch. TorchDrug benchmarks a variety of important tasks in drug discovery, including molecular property prediction, pretrained molecular representations, de novo molecular design and optimization, retrosynthsis prediction, and biomedical knowledge graph reasoning. State-of-the-art techniques based on geometric deep learning (or graph machine learning), deep generative models, reinforcement learning and knowledge graph reasoning are implemented for these tasks. TorchDrug features a hierarchical interface that facilitates customization from both novices and experts in this domain. Tutorials, benchmark results and documentation are available at https://torchdrug.ai. Code is released under Apache License 2.0.