ProteinWeaver: A Divide-and-Assembly Approach for Protein Backbone Design

Nature creates diverse proteins through a `divide and assembly' strategy. Inspired by this idea, we introduce ProteinWeaver, a two-stage framework for protein backbone design. Our method first generates individual protein domains and then employs an SE(3) diffusion model to flexibly assemble these domains. A key challenge lies in the assembling step, given the complex and rugged nature of the inter-domain interaction landscape. To address this challenge, we employ preference alignment to discern complex relationships between structure and interaction landscapes through comparative analysis of generated samples. Comprehensive experiments demonstrate that ProteinWeaver: (1) generates high-quality, novel protein backbones through versatile domain assembly; (2) outperforms RFdiffusion, the current state-of-the-art in backbone design, by 13\% and 39\% for long-chain proteins; (3) shows the potential for cooperative function design through illustrative case studies. To sum up, by introducing a `divide-and-assembly' paradigm, ProteinWeaver advances protein engineering and opens new avenues for functional protein design.

DPLM-2: A Multimodal Diffusion Protein Language Model

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.

ProteinBench: A Holistic Evaluation of Protein Foundation Models

Recent years have witnessed a surge in the development of protein foundation models, significantly improving performance in protein prediction and generative tasks ranging from 3D structure prediction and protein design to conformational dynamics. However, the capabilities and limitations associated with these models remain poorly understood due to the absence of a unified evaluation framework. To fill this gap, we introduce ProteinBench, a holistic evaluation framework designed to enhance the transparency of protein foundation models. Our approach consists of three key components: (i) A taxonomic classification of tasks that broadly encompass the main challenges in the protein domain, based on the relationships between different protein modalities; (ii) A multi-metric evaluation approach that assesses performance across four key dimensions: quality, novelty, diversity, and robustness; and (iii) In-depth analyses from various user objectives, providing a holistic view of model performance. Our comprehensive evaluation of protein foundation models reveals several key findings that shed light on their current capabilities and limitations. To promote transparency and facilitate further research, we release the evaluation dataset, code, and a public leaderboard publicly for further analysis and a general modular toolkit. We intend for ProteinBench to be a living benchmark for establishing a standardized, in-depth evaluation framework for protein foundation models, driving their development and application while fostering collaboration within the field.

Dynamic Multi-Objective Lion Swarm Optimization with Multi-strategy Fusion: An application in 6R robot trajectory

The advancement of industrialization has fostered innovative swarm intelligence algorithms, with Lion Swarm Optimization (LSO) being notable for its robustness and efficiency. However, multi-objective variants of LSO struggle with poor initialization, local optima entrapment, and slow adaptation to dynamic environments. This study proposes a Dynamic Multi-Objective Lion Swarm Optimization with Multi-strategy Fusion (MF-DMOLSO) to overcome these challenges. MF-DMOLSO includes an initialization unit using chaotic mapping, a position update unit enhancing behavior patterns based on non-domination and diversity, and an external archive update unit. Evaluations on benchmark functions showed MF-DMOLSO outperformed existing algorithms achieving an accuracy that exceeds the comparison algorithm by 90%. Applied to 6R robot trajectory planning, MF-DMOLSO optimized running time and maximum acceleration to 8.3s and 0.3pi rad/s^2, respectively, achieving a set coverage rate of 70.97% compared to 2% by multi-objective particle swarm optimization, thus improving efficiency and reducing mechanical dither.

Diffusion Language Models Are Versatile Protein Learners

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.

Learning Harmonic Molecular Representations on Riemannian Manifold

Molecular representation learning plays a crucial role in AI-assisted drug discovery research. Encoding 3D molecular structures through Euclidean neural networks has become the prevailing method in the geometric deep learning community. However, the equivariance constraints and message passing in Euclidean space may limit the network expressive power. In this work, we propose a Harmonic Molecular Representation learning (HMR) framework, which represents a molecule using the Laplace-Beltrami eigenfunctions of its molecular surface. HMR offers a multi-resolution representation of molecular geometric and chemical features on 2D Riemannian manifold. We also introduce a harmonic message passing method to realize efficient spectral message passing over the surface manifold for better molecular encoding. Our proposed method shows comparable predictive power to current models in small molecule property prediction, and outperforms the state-of-the-art deep learning models for ligand-binding protein pocket classification and the rigid protein docking challenge, demonstrating its versatility in molecular representation learning.

On Pre-trained Language Models for Antibody

Antibodies are vital proteins offering robust protection for the human body from pathogens. The development of general protein and antibody-specific pre-trained language models both facilitate antibody prediction tasks. However, few studies comprehensively explore the representation capability of distinct pre-trained language models on different antibody problems. Here, to investigate the problem, we aim to answer the following key questions: (1) How do pre-trained language models perform in antibody tasks with different specificity? (2) How many benefits will the model gain if we introduce the specific biological mechanism to the pre-training process? (3) Do the learned antibody pre-trained representations make sense in real-world antibody problems, like drug discovery and immune process understanding? Previously, no benchmark available largely hindered the study to answer these questions. To facilitate the investigation, we provide an AnTibody Understanding Evaluation (ATUE) benchmark. We comprehensively evaluate the performance of protein pre-trained language models by empirical study along with conclusions and new insights. Our ATUE and code are released at https://github.com/dqwang122/EATLM.

Accelerating Antimicrobial Peptide Discovery with Latent Sequence-Structure Model

Antimicrobial peptide (AMP) is a promising therapy in the treatment of broad-spectrum antibiotics and drug-resistant infections. Recently, an increasing number of researchers have been introducing deep generative models to accelerate AMP discovery. However, current studies mainly focus on sequence attributes and ignore structure information, which is important in AMP biological functions. In this paper, we propose a latent sequence-structure model for AMPs (LSSAMP) with multi-scale VQ-VAE to incorporate secondary structures. By sampling in the latent space, LSSAMP can simultaneously generate peptides with ideal sequence attributes and secondary structures. Experimental results show that the peptides generated by LSSAMP have a high probability of AMP, and two of the 21 candidates have been verified to have good antimicrobial activity. Our model will be released to help create high-quality AMP candidates for follow-up biological experiments and accelerate the whole AMP discovery.

Task-Free Continual Learning via Online Discrepancy Distance Learning

Learning from non-stationary data streams, also called Task-Free Continual Learning (TFCL) remains challenging due to the absence of explicit task information. Although recently some methods have been proposed for TFCL, they lack theoretical guarantees. Moreover, forgetting analysis during TFCL was not studied theoretically before. This paper develops a new theoretical analysis framework which provides generalization bounds based on the discrepancy distance between the visited samples and the entire information made available for training the model. This analysis gives new insights into the forgetting behaviour in classification tasks. Inspired by this theoretical model, we propose a new approach enabled by the dynamic component expansion mechanism for a mixture model, namely the Online Discrepancy Distance Learning (ODDL). ODDL estimates the discrepancy between the probabilistic representation of the current memory buffer and the already accumulated knowledge and uses it as the expansion signal to ensure a compact network architecture with optimal performance. We then propose a new sample selection approach that selectively stores the most relevant samples into the memory buffer through the discrepancy-based measure, further improving the performance. We perform several TFCL experiments with the proposed methodology, which demonstrate that the proposed approach achieves the state of the art performance.

Continual Variational Autoencoder Learning via Online Cooperative Memorization

Due to their inference, data representation and reconstruction properties, Variational Autoencoders (VAE) have been successfully used in continual learning classification tasks. However, their ability to generate images with specifications corresponding to the classes and databases learned during Continual Learning (CL) is not well understood and catastrophic forgetting remains a significant challenge. In this paper, we firstly analyze the forgetting behaviour of VAEs by developing a new theoretical framework that formulates CL as a dynamic optimal transport problem. This framework proves approximate bounds to the data likelihood without requiring the task information and explains how the prior knowledge is lost during the training process. We then propose a novel memory buffering approach, namely the Online Cooperative Memorization (OCM) framework, which consists of a Short-Term Memory (STM) that continually stores recent samples to provide future information for the model, and a Long-Term Memory (LTM) aiming to preserve a wide diversity of samples. The proposed OCM transfers certain samples from STM to LTM according to the information diversity selection criterion without requiring any supervised signals. The OCM framework is then combined with a dynamic VAE expansion mixture network for further enhancing its performance.