The introduction of models like RFDiffusionAA, AlphaFold3, AlphaProteo, and Chai1 has revolutionized protein structure modeling and interaction prediction, primarily from a binding perspective, focusing on creating ideal lock-and-key models. However, these methods can fall short for enzyme-substrate interactions, where perfect binding models are rare, and induced fit states are more common. To address this, we shift to a functional perspective for enzyme design, where the enzyme function is defined by the reaction it catalyzes. Here, we introduce \textsc{GENzyme}, a \textit{de novo} enzyme design model that takes a catalytic reaction as input and generates the catalytic pocket, full enzyme structure, and enzyme-substrate binding complex. \textsc{GENzyme} is an end-to-end, three-staged model that integrates (1) a catalytic pocket generation and sequence co-design module, (2) a pocket inpainting and enzyme inverse folding module, and (3) a binding and screening module to optimize and predict enzyme-substrate complexes. The entire design process is driven by the catalytic reaction being targeted. This reaction-first approach allows for more accurate and biologically relevant enzyme design, potentially surpassing structure-based and binding-focused models in creating enzymes capable of catalyzing specific reactions. We provide \textsc{GENzyme} code at https://github.com/WillHua127/GENzyme.

Antibodies are essential proteins responsible for immune responses in organisms, capable of specifically recognizing antigen molecules of pathogens. Recent advances in generative models have significantly enhanced rational antibody design. However, existing methods mainly create antibodies from scratch without template constraints, leading to model optimization challenges and unnatural sequences. To address these issues, we propose a retrieval-augmented diffusion framework, termed RADAb, for efficient antibody design. Our method leverages a set of structural homologous motifs that align with query structural constraints to guide the generative model in inversely optimizing antibodies according to desired design criteria. Specifically, we introduce a structure-informed retrieval mechanism that integrates these exemplar motifs with the input backbone through a novel dual-branch denoising module, utilizing both structural and evolutionary information. Additionally, we develop a conditional diffusion model that iteratively refines the optimization process by incorporating both global context and local evolutionary conditions. Our approach is agnostic to the choice of generative models. Empirical experiments demonstrate that our method achieves state-ofthe-art performance in multiple antibody inverse folding and optimization tasks, offering a new perspective on biomolecular generative models. Antibodies, essential Y-shaped proteins in the immune system, are pivotal for recognizing and neutralizing specific pathogens known as antigens.

Enzyme design is a critical area in biotechnology, with applications ranging from drug development to synthetic biology. Traditional methods for enzyme function prediction or protein binding pocket design often fall short in capturing the dynamic and complex nature of enzyme-substrate interactions, particularly in catalytic processes. To address the challenges, we introduce EnzymeFlow, a generative model that employs flow matching with hierarchical pre-training and enzyme-reaction co-evolution to generate catalytic pockets for specific substrates and catalytic reactions. Additionally, we introduce a large-scale, curated, and validated dataset of enzyme-reaction pairs, specifically designed for the catalytic pocket generation task, comprising a total of $328,192$ pairs. By incorporating evolutionary dynamics and reaction-specific adaptations, EnzymeFlow becomes a powerful model for designing enzyme pockets, which is capable of catalyzing a wide range of biochemical reactions. Experiments on the new dataset demonstrate the model's effectiveness in designing high-quality, functional enzyme catalytic pockets, paving the way for advancements in enzyme engineering and synthetic biology. We provide EnzymeFlow code at https://github.com/WillHua127/EnzymeFlow with notebook demonstration at https://github.com/WillHua127/EnzymeFlow/blob/main/enzymeflow_demo.ipynb.

Graph Neural Networks (GNNs) have gained considerable traction for their capability to effectively process topological data, yet their interpretability remains a critical concern. Current interpretation methods are dominated by post-hoc explanations to provide a transparent and intuitive understanding of GNNs. However, they have limited performance in interpreting complicated subgraphs and can't utilize the explanation to advance GNN predictions. On the other hand, transparent GNN models are proposed to capture critical subgraphs. While such methods could improve GNN predictions, they usually don't perform well on explanations. Thus, it is desired for a new strategy to better couple GNN explanation and prediction. In this study, we have developed a novel interpretable causal GNN framework that incorporates retrieval-based causal learning with Graph Information Bottleneck (GIB) theory. The framework could semi-parametrically retrieve crucial subgraphs detected by GIB and compress the explanatory subgraphs via a causal module. The framework was demonstrated to consistently outperform state-of-the-art methods, and to achieve 32.71\% higher precision on real-world explanation scenarios with diverse explanation types. More importantly, the learned explanations were shown able to also improve GNN prediction performance.

Protein-protein interactions (PPIs) are crucial in regulating numerous cellular functions, including signal transduction, transportation, and immune defense. As the accuracy of multi-chain protein complex structure prediction improves, the challenge has shifted towards effectively navigating the vast complex universe to identify potential PPIs. Herein, we propose PPIretrieval, the first deep learning-based model for protein-protein interaction exploration, which leverages existing PPI data to effectively search for potential PPIs in an embedding space, capturing rich geometric and chemical information of protein surfaces. When provided with an unseen query protein with its associated binding site, PPIretrieval effectively identifies a potential binding partner along with its corresponding binding site in an embedding space, facilitating the formation of protein-protein complexes.

Molecular dynamics simulations have emerged as a fundamental instrument for studying biomolecules. At the same time, it is desirable to perform simulations of a collection of particles under various conditions in which the molecules can fluctuate. In this paper, we explore and adapt the soft prompt-based learning method to molecular dynamics tasks. Our model can remarkably generalize to unseen and out-of-distribution scenarios with limited training data. While our work focuses on temperature as a test case, the versatility of our approach allows for efficient simulation through any continuous dynamic conditions, such as pressure and volumes. Our framework has two stages: 1) Pre-trains with data mixing technique, augments molecular structure data and temperature prompts, then applies a curriculum learning method by increasing the ratio of them smoothly. 2) Meta-learning-based fine-tuning framework improves sample-efficiency of fine-tuning process and gives the soft prompt-tuning better initialization points. Comprehensive experiments reveal that our framework excels in accuracy for in-domain data and demonstrates strong generalization capabilities for unseen and out-of-distribution samples.

The wide application of smart devices enables the availability of multimodal data, which can be utilized in many tasks. In the field of multimodal sentiment analysis (MSA), most previous works focus on exploring intra- and inter-modal interactions. However, training a network with cross-modal information (language, visual, audio) is still challenging due to the modality gap, and existing methods still cannot ensure to sufficiently learn intra-/inter-modal dynamics. Besides, while learning dynamics within each sample draws great attention, the learning of inter-class relationships is neglected. Moreover, the size of datasets limits the generalization ability of existing methods. To address the afore-mentioned issues, we propose a novel framework HyCon for hybrid contrastive learning of tri-modal representation. Specifically, we simultaneously perform intra-/inter-modal contrastive learning and semi-contrastive learning (that is why we call it hybrid contrastive learning), with which the model can fully explore cross-modal interactions, preserve inter-class relationships and reduce the modality gap. Besides, a refinement term is devised to prevent the model falling into a sub-optimal solution. Moreover, HyCon can naturally generate a large amount of training pairs for better generalization and reduce the negative effect of limited datasets. Extensive experiments on public datasets demonstrate that our proposed method outperforms existing works.

Constructing appropriate representations of molecules lies at the core of numerous tasks such as material science, chemistry and drug designs. Recent researches abstract molecules as attributed graphs and employ graph neural networks (GNN) for molecular representation learning, which have made remarkable achievements in molecular graph modeling. Albeit powerful, current models either are based on local aggregation operations and thus miss higher-order graph properties or focus on only node information without fully using the edge information. For this sake, we propose a Communicative Message Passing Transformer (CoMPT) neural network to improve the molecular graph representation by reinforcing message interactions between nodes and edges based on the Transformer architecture. Unlike the previous transformer-style GNNs that treat molecules as fully connected graphs, we introduce a message diffusion mechanism to leverage the graph connectivity inductive bias and reduce the message enrichment explosion. Extensive experiments demonstrated that the proposed model obtained superior performances (around 4$\%$ on average) against state-of-the-art baselines on seven chemical property datasets (graph-level tasks) and two chemical shift datasets (node-level tasks). Further visualization studies also indicated a better representation capacity achieved by our model.

Relation prediction for knowledge graphs aims at predicting missing relationships between entities. Despite the importance of inductive relation prediction, most previous works are limited to a transductive setting and cannot process previously unseen entities. The recent proposed subgraph-based relation reasoning models provided alternatives to predict links from the subgraph structure surrounding a candidate triplet inductively. However, we observe that these methods often neglect the directed nature of the extracted subgraph and weaken the role of relation information in the subgraph modeling. As a result, they fail to effectively handle the asymmetric/anti-symmetric triplets and produce insufficient embeddings for the target triplets. To this end, we introduce a \textbf{C}\textbf{o}mmunicative \textbf{M}essage \textbf{P}assing neural network for \textbf{I}nductive re\textbf{L}ation r\textbf{E}asoning, \textbf{CoMPILE}, that reasons over local directed subgraph structures and has a vigorous inductive bias to process entity-independent semantic relations. In contrast to existing models, CoMPILE strengthens the message interactions between edges and entitles through a communicative kernel and enables a sufficient flow of relation information. Moreover, we demonstrate that CoMPILE can naturally handle asymmetric/anti-symmetric relations without the need for explosively increasing the number of model parameters by extracting the directed enclosing subgraphs. Extensive experiments show substantial performance gains in comparison to state-of-the-art methods on commonly used benchmark datasets with variant inductive settings.