arXiv subjects

Zaixi Zhang

Publications and source records attributed to Zaixi Zhang.

At least 37 records · Page 2Linked to original sources

arXiv2024

DeltaDock: A Unified Framework for Accurate, Efficient, and Physically Reliable Molecular Docking

Molecular docking, a technique for predicting ligand binding poses, is crucial in structure-based drug design for understanding protein-ligand interactions. Recent advancements in docking methods, particularly those leveraging geometric deep learning (GDL), have demonstrated significant efficiency and accuracy advantages over traditional sampling methods. Despite these advancements, current methods are often tailored for specific docking settings, and limitations such as the neglect of protein side-chain structures, difficulties in handling large binding pockets, and challenges in predicting physically valid structures exist. To accommodate various docking settings and achieve accurate, efficient, and physically reliable docking, we propose a novel two-stage docking framework, DeltaDock, consisting of pocket prediction and site-specific docking. We innovatively reframe the pocket prediction task as a pocket-ligand alignment problem rather than direct prediction in the first stage. Then we follow a bi-level coarse-to-fine iterative refinement process to perform site-specific docking. Comprehensive experiments demonstrate the superior performance of DeltaDock. Notably, in the blind docking setting, DeltaDock achieves a 31\% relative improvement over the docking success rate compared with the previous state-of-the-art GDL model. With the consideration of physical validity, this improvement increases to about 300\%.

q-bio.BM↗

arXiv2024

Generalized Protein Pocket Generation with Prior-Informed Flow Matching

Designing ligand-binding proteins, such as enzymes and biosensors, is essential in bioengineering and protein biology. One critical step in this process involves designing protein pockets, the protein interface binding with the ligand. Current approaches to pocket generation often suffer from time-intensive physical computations or template-based methods, as well as compromised generation quality due to the overlooking of domain knowledge. To tackle these challenges, we propose PocketFlow, a generative model that incorporates protein-ligand interaction priors based on flow matching. During training, PocketFlow learns to model key types of protein-ligand interactions, such as hydrogen bonds. In the sampling, PocketFlow leverages multi-granularity guidance (overall binding affinity and interaction geometry constraints) to facilitate generating high-affinity and valid pockets. Extensive experiments show that PocketFlow outperforms baselines on multiple benchmarks, e.g., achieving an average improvement of 1.29 in Vina Score and 0.05 in scRMSD. Moreover, modeling interactions make PocketFlow a generalized generative model across multiple ligand modalities, including small molecules, peptides, and RNA.

q-bio.BM↗

arXiv2024

FlexSBDD: Structure-Based Drug Design with Flexible Protein Modeling

Structure-based drug design (SBDD), which aims to generate 3D ligand molecules binding to target proteins, is a fundamental task in drug discovery. Existing SBDD methods typically treat protein as rigid and neglect protein structural change when binding with ligand molecules, leading to a big gap with real-world scenarios and inferior generation qualities (e.g., many steric clashes). To bridge the gap, we propose FlexSBDD, a deep generative model capable of accurately modeling the flexible protein-ligand complex structure for ligand molecule generation. FlexSBDD adopts an efficient flow matching framework and leverages E(3)-equivariant network with scalar-vector dual representation to model dynamic structural changes. Moreover, novel data augmentation schemes based on structure relaxation/sidechain repacking are adopted to boost performance. Extensive experiments demonstrate that FlexSBDD achieves state-of-the-art performance in generating high-affinity molecules and effectively modeling the protein's conformation change to increase favorable protein-ligand interactions (e.g., Hydrogen bonds) and decrease steric clashes.

q-bio.BM↗

arXiv2024

Towards Few-shot Self-explaining Graph Neural Networks

Recent advancements in Graph Neural Networks (GNNs) have spurred an upsurge of research dedicated to enhancing the explainability of GNNs, particularly in critical domains such as medicine. A promising approach is the self-explaining method, which outputs explanations along with predictions. However, existing self-explaining models require a large amount of training data, rendering them unavailable in few-shot scenarios. To address this challenge, in this paper, we propose a Meta-learned Self-Explaining GNN (MSE-GNN), a novel framework that generates explanations to support predictions in few-shot settings. MSE-GNN adopts a two-stage self-explaining structure, consisting of an explainer and a predictor. Specifically, the explainer first imitates the attention mechanism of humans to select the explanation subgraph, whereby attention is naturally paid to regions containing important characteristics. Subsequently, the predictor mimics the decision-making process, which makes predictions based on the generated explanation. Moreover, with a novel meta-training process and a designed mechanism that exploits task information, MSE-GNN can achieve remarkable performance on new few-shot tasks. Extensive experimental results on four datasets demonstrate that MSE-GNN can achieve superior performance on prediction tasks while generating high-quality explanations compared with existing methods. The code is publicly available at https://github.com/jypeng28/MSE-GNN.

cs.LG↗

arXiv2024

What Improves the Generalization of Graph Transformers? A Theoretical Dive into the Self-attention and Positional Encoding

Graph Transformers, which incorporate self-attention and positional encoding, have recently emerged as a powerful architecture for various graph learning tasks. Despite their impressive performance, the complex non-convex interactions across layers and the recursive graph structure have made it challenging to establish a theoretical foundation for learning and generalization. This study introduces the first theoretical investigation of a shallow Graph Transformer for semi-supervised node classification, comprising a self-attention layer with relative positional encoding and a two-layer perceptron. Focusing on a graph data model with discriminative nodes that determine node labels and non-discriminative nodes that are class-irrelevant, we characterize the sample complexity required to achieve a desirable generalization error by training with stochastic gradient descent (SGD). This paper provides the quantitative characterization of the sample complexity and number of iterations for convergence dependent on the fraction of discriminative nodes, the dominant patterns, and the initial model errors. Furthermore, we demonstrate that self-attention and positional encoding enhance generalization by making the attention map sparse and promoting the core neighborhood during training, which explains the superior feature representation of Graph Transformers. Our theoretical results are supported by empirical experiments on synthetic and real-world benchmarks.

cs.LG↗

arXiv2024

Structure-based Drug Design Benchmark: Do 3D Methods Really Dominate?

Currently, the field of structure-based drug design is dominated by three main types of algorithms: search-based algorithms, deep generative models, and reinforcement learning. While existing works have typically focused on comparing models within a single algorithmic category, cross-algorithm comparisons remain scarce. In this paper, to fill the gap, we establish a benchmark to evaluate the performance of sixteen models across these different algorithmic foundations by assessing the pharmaceutical properties of the generated molecules and their docking affinities with specified target proteins. We highlight the unique advantages of each algorithmic approach and offer recommendations for the design of future SBDD models. We emphasize that 1D/2D ligand-centric drug design methods can be used in SBDD by treating the docking function as a black-box oracle, which is typically neglected. The empirical results show that 1D/2D methods achieve competitive performance compared with 3D-based methods that use the 3D structure of the target protein explicitly. Also, AutoGrow4, a 2D molecular graph-based genetic algorithm, dominates SBDD in terms of optimization ability. The relevant code is available in https://github.com/zkysfls/2024-sbdd-benchmark.

cs.LG↗

arXiv2024

Deep Geometry Handling and Fragment-wise Molecular 3D Graph Generation

Most earlier 3D structure-based molecular generation approaches follow an atom-wise paradigm, incrementally adding atoms to a partially built molecular fragment within protein pockets. These methods, while effective in designing tightly bound ligands, often overlook other essential properties such as synthesizability. The fragment-wise generation paradigm offers a promising solution. However, a common challenge across both atom-wise and fragment-wise methods lies in their limited ability to co-design plausible chemical and geometrical structures, resulting in distorted conformations. In response to this challenge, we introduce the Deep Geometry Handling protocol, a more abstract design that extends the design focus beyond the model architecture. Through a comprehensive review of existing geometry-related models and their protocols, we propose a novel hybrid strategy, culminating in the development of FragGen - a geometry-reliable, fragment-wise molecular generation method. FragGen marks a significant leap forward in the quality of generated geometry and the synthesis accessibility of molecules. The efficacy of FragGen is further validated by its successful application in designing type II kinase inhibitors at the nanomolar level.

physics.chem-ph↗

arXiv2024

FedGT: Federated Node Classification with Scalable Graph Transformer

Graphs are widely used to model relational data. As graphs are getting larger and larger in real-world scenarios, there is a trend to store and compute subgraphs in multiple local systems. For example, recently proposed \emph{subgraph federated learning} methods train Graph Neural Networks (GNNs) distributively on local subgraphs and aggregate GNN parameters with a central server. However, existing methods have the following limitations: (1) The links between local subgraphs are missing in subgraph federated learning. This could severely damage the performance of GNNs that follow message-passing paradigms to update node/edge features. (2) Most existing methods overlook the subgraph heterogeneity issue, brought by subgraphs being from different parts of the whole graph. To address the aforementioned challenges, we propose a scalable \textbf{Fed}erated \textbf{G}raph \textbf{T}ransformer (\textbf{FedGT}) in the paper. Firstly, we design a hybrid attention scheme to reduce the complexity of the Graph Transformer to linear while ensuring a global receptive field with theoretical bounds. Specifically, each node attends to the sampled local neighbors and a set of curated global nodes to learn both local and global information and be robust to missing links. The global nodes are dynamically updated during training with an online clustering algorithm to capture the data distribution of the corresponding local subgraph. Secondly, FedGT computes clients' similarity based on the aligned global nodes with optimal transport. The similarity is then used to perform weighted averaging for personalized aggregation, which well addresses the data heterogeneity problem. Moreover, local differential privacy is applied to further protect the privacy of clients. Finally, extensive experimental results on 6 datasets and 2 subgraph settings demonstrate the superiority of FedGT.

cs.LG↗

arXiv2024

Binding-Adaptive Diffusion Models for Structure-Based Drug Design

Structure-based drug design (SBDD) aims to generate 3D ligand molecules that bind to specific protein targets. Existing 3D deep generative models including diffusion models have shown great promise for SBDD. However, it is complex to capture the essential protein-ligand interactions exactly in 3D space for molecular generation. To address this problem, we propose a novel framework, namely Binding-Adaptive Diffusion Models (BindDM). In BindDM, we adaptively extract subcomplex, the essential part of binding sites responsible for protein-ligand interactions. Then the selected protein-ligand subcomplex is processed with SE(3)-equivariant neural networks, and transmitted back to each atom of the complex for augmenting the target-aware 3D molecule diffusion generation with binding interaction information. We iterate this hierarchical complex-subcomplex process with cross-hierarchy interaction node for adequately fusing global binding context between the complex and its corresponding subcomplex. Empirical studies on the CrossDocked2020 dataset show BindDM can generate molecules with more realistic 3D structures and higher binding affinities towards the protein targets, with up to -5.92 Avg. Vina Score, while maintaining proper molecular properties. Our code is available at https://github.com/YangLing0818/BindDM

q-bio.BM↗

arXiv2023

Multi-scale Iterative Refinement towards Robust and Versatile Molecular Docking

Molecular docking is a key computational tool utilized to predict the binding conformations of small molecules to protein targets, which is fundamental in the design of novel drugs. Despite recent advancements in geometric deep learning-based approaches leading to improvements in blind docking efficiency, these methods have encountered notable challenges, such as limited generalization performance on unseen proteins, the inability to concurrently address the settings of blind docking and site-specific docking, and the frequent occurrence of physical implausibilities such as inter-molecular steric clash. In this study, we introduce DeltaDock, a robust and versatile framework designed for efficient molecular docking to overcome these challenges. DeltaDock operates in a two-step process: rapid initial complex structures sampling followed by multi-scale iterative refinement of the initial structures. In the initial stage, to sample accurate structures with high efficiency, we develop a ligand-dependent binding site prediction model founded on large protein models and graph neural networks. This model is then paired with GPU-accelerated sampling algorithms. The sampled structures are updated using a multi-scale iterative refinement module that captures both protein-ligand atom-atom interactions and residue-atom interactions in the following stage. Distinct from previous geometric deep learning methods that are conditioned on the blind docking setting, DeltaDock demonstrates superior performance in both blind docking and site-specific docking settings. Comprehensive experimental results reveal that DeltaDock consistently surpasses baseline methods in terms of docking accuracy. Furthermore, it displays remarkable generalization capabilities and proficiency for predicting physically valid structures, thereby attesting to its robustness and reliability in various scenarios.

q-bio.BM↗

arXiv2023

Sparse Attention-Based Neural Networks for Code Classification

Categorizing source codes accurately and efficiently is a challenging problem in real-world programming education platform management. In recent years, model-based approaches utilizing abstract syntax trees (ASTs) have been widely applied to code classification tasks. We introduce an approach named the Sparse Attention-based neural network for Code Classification (SACC) in this paper. The approach involves two main steps: In the first step, source code undergoes syntax parsing and preprocessing. The generated abstract syntax tree is split into sequences of subtrees and then encoded using a recursive neural network to obtain a high-dimensional representation. This step simultaneously considers both the logical structure and lexical level information contained within the code. In the second step, the encoded sequences of subtrees are fed into a Transformer model that incorporates sparse attention mechanisms for the purpose of classification. This method efficiently reduces the computational cost of the self-attention mechanisms, thus improving the training speed while preserving effectiveness. Our work introduces a carefully designed sparse attention pattern that is specifically designed to meet the unique needs of code classification tasks. This design helps reduce the influence of redundant information and enhances the overall performance of the model. Finally, we also deal with problems in previous related research, which include issues like incomplete classification labels and a small dataset size. We annotated the CodeNet dataset with algorithm-related labeling categories, which contains a significantly large amount of data. Extensive comparative experimental results demonstrate the effectiveness and efficiency of SACC for the code classification tasks.

cs.PL↗

arXiv2023

AdaptSSR: Pre-training User Model with Augmentation-Adaptive Self-Supervised Ranking

User modeling, which aims to capture users' characteristics or interests, heavily relies on task-specific labeled data and suffers from the data sparsity issue. Several recent studies tackled this problem by pre-training the user model on massive user behavior sequences with a contrastive learning task. Generally, these methods assume different views of the same behavior sequence constructed via data augmentation are semantically consistent, i.e., reflecting similar characteristics or interests of the user, and thus maximizing their agreement in the feature space. However, due to the diverse interests and heavy noise in user behaviors, existing augmentation methods tend to lose certain characteristics of the user or introduce noisy behaviors. Thus, forcing the user model to directly maximize the similarity between the augmented views may result in a negative transfer. To this end, we propose to replace the contrastive learning task with a new pretext task: Augmentation-Adaptive SelfSupervised Ranking (AdaptSSR), which alleviates the requirement of semantic consistency between the augmented views while pre-training a discriminative user model. Specifically, we adopt a multiple pairwise ranking loss which trains the user model to capture the similarity orders between the implicitly augmented view, the explicitly augmented view, and views from other users. We further employ an in-batch hard negative sampling strategy to facilitate model training. Moreover, considering the distinct impacts of data augmentation on different behavior sequences, we design an augmentation-adaptive fusion mechanism to automatically adjust the similarity order constraint applied to each sample based on the estimated similarity between the augmented views. Extensive experiments on both public and industrial datasets with six downstream tasks verify the effectiveness of AdaptSSR.

cs.IR↗

arXiv2023

Full-Atom Protein Pocket Design via Iterative Refinement

The design of \emph{de novo} functional proteins that bind specific ligand molecules is paramount in therapeutics and bio-engineering. A critical yet formidable task in this endeavor is the design of the protein pocket, which is the cavity region of the protein where the ligand binds. Current methods are plagued by inefficient generation, inadequate context modeling of the ligand molecule, and the inability to generate side-chain atoms. Here, we present the Full-Atom Iterative Refinement (FAIR) method, designed to address these challenges by facilitating the co-design of protein pocket sequences, specifically residue types, and their corresponding 3D structures. FAIR operates in two steps, proceeding in a coarse-to-fine manner (transitioning from protein backbone to atoms, including side chains) for a full-atom generation. In each iteration, all residue types and structures are simultaneously updated, a process termed full-shot refinement. In the initial stage, the residue types and backbone coordinates are refined using a hierarchical context encoder, complemented by two structure refinement modules that capture both inter-residue and pocket-ligand interactions. The subsequent stage delves deeper, modeling the side-chain atoms of the pockets and updating residue types to ensure sequence-structure congruence. Concurrently, the structure of the binding ligand is refined across iterations to accommodate its inherent flexibility. Comprehensive experiments show that FAIR surpasses existing methods in designing superior pocket sequences and structures, producing average improvement exceeding 10\% in AAR and RMSD metrics. FAIR is available at \url{https://github.com/zaixizhang/FAIR}.

q-bio.BM↗

arXiv2023

Learning Subpocket Prototypes for Generalizable Structure-based Drug Design

Generating molecules with high binding affinities to target proteins (a.k.a. structure-based drug design) is a fundamental and challenging task in drug discovery. Recently, deep generative models have achieved remarkable success in generating 3D molecules conditioned on the protein pocket. However, most existing methods consider molecular generation for protein pockets independently while neglecting the underlying connections such as subpocket-level similarities. Subpockets are the local protein environments of ligand fragments and pockets with similar subpockets may bind the same molecular fragment (motif) even though their overall structures are different. Therefore, the trained models can hardly generalize to unseen protein pockets in real-world applications. In this paper, we propose a novel method DrugGPS for generalizable structure-based drug design. With the biochemical priors, we propose to learn subpocket prototypes and construct a global interaction graph to model the interactions between subpocket prototypes and molecular motifs. Moreover, a hierarchical graph transformer encoder and motif-based 3D molecule generation scheme are used to improve the model's performance. The experimental results show that our model consistently outperforms baselines in generating realistic drug candidates with high affinities in challenging out-of-distribution settings.

q-bio.BM↗

arXiv2023

An Equivariant Generative Framework for Molecular Graph-Structure Co-Design

Designing molecules with desirable physiochemical properties and functionalities is a long-standing challenge in chemistry, material science, and drug discovery. Recently, machine learning-based generative models have emerged as promising approaches for \emph{de novo} molecule design. However, further refinement of methodology is highly desired as most existing methods lack unified modeling of 2D topology and 3D geometry information and fail to effectively learn the structure-property relationship for molecule design. Here we present MolCode, a roto-translation equivariant generative framework for \underline{Mol}ecular graph-structure \underline{Co-de}sign. In MolCode, 3D geometric information empowers the molecular 2D graph generation, which in turn helps guide the prediction of molecular 3D structure. Extensive experimental results show that MolCode outperforms previous methods on a series of challenging tasks including \emph{de novo} molecule design, targeted molecule discovery, and structure-based drug design. Particularly, MolCode not only consistently generates valid (99.95$\%$ Validity) and diverse (98.75$\%$ Uniqueness) molecular graphs/structures with desirable properties, but also generate drug-like molecules with high affinity to target proteins (61.8$\%$ high-affinity ratio), which demonstrates MolCode's potential applications in material design and drug discovery. Our extensive investigation reveals that the 2D topology and 3D geometry contain intrinsically complementary information in molecule design, and provide new insights into machine learning-based molecule representation and generation.

q-bio.BM↗

arXiv2023

Backdoor Defense via Deconfounded Representation Learning

Deep neural networks (DNNs) are recently shown to be vulnerable to backdoor attacks, where attackers embed hidden backdoors in the DNN model by injecting a few poisoned examples into the training dataset. While extensive efforts have been made to detect and remove backdoors from backdoored DNNs, it is still not clear whether a backdoor-free clean model can be directly obtained from poisoned datasets. In this paper, we first construct a causal graph to model the generation process of poisoned data and find that the backdoor attack acts as the confounder, which brings spurious associations between the input images and target labels, making the model predictions less reliable. Inspired by the causal understanding, we propose the Causality-inspired Backdoor Defense (CBD), to learn deconfounded representations for reliable classification. Specifically, a backdoored model is intentionally trained to capture the confounding effects. The other clean model dedicates to capturing the desired causal effects by minimizing the mutual information with the confounding representations from the backdoored model and employing a sample-wise re-weighting scheme. Extensive experiments on multiple benchmark datasets against 6 state-of-the-art attacks verify that our proposed defense method is effective in reducing backdoor threats while maintaining high accuracy in predicting benign samples. Further analysis shows that CBD can also resist potential adaptive attacks. The code is available at \url{https://github.com/zaixizhang/CBD}.

cs.AI↗

arXiv2022

Untargeted Attack against Federated Recommendation Systems via Poisonous Item Embeddings and the Defense

Federated recommendation (FedRec) can train personalized recommenders without collecting user data, but the decentralized nature makes it susceptible to poisoning attacks. Most previous studies focus on the targeted attack to promote certain items, while the untargeted attack that aims to degrade the overall performance of the FedRec system remains less explored. In fact, untargeted attacks can disrupt the user experience and bring severe financial loss to the service provider. However, existing untargeted attack methods are either inapplicable or ineffective against FedRec systems. In this paper, we delve into the untargeted attack and its defense for FedRec systems. (i) We propose ClusterAttack, a novel untargeted attack method. It uploads poisonous gradients that converge the item embeddings into several dense clusters, which make the recommender generate similar scores for these items in the same cluster and perturb the ranking order. (ii) We propose a uniformity-based defense mechanism (UNION) to protect FedRec systems from such attacks. We design a contrastive learning task that regularizes the item embeddings toward a uniform distribution. Then the server filters out these malicious gradients by estimating the uniformity of updated item embeddings. Experiments on two public datasets show that ClusterAttack can effectively degrade the performance of FedRec systems while circumventing many defense methods, and UNION can improve the resistance of the system against various untargeted attacks, including our ClusterAttack.

cs.IR↗

arXiv2022

FLDetector: Defending Federated Learning Against Model Poisoning Attacks via Detecting Malicious Clients

Federated learning (FL) is vulnerable to model poisoning attacks, in which malicious clients corrupt the global model via sending manipulated model updates to the server. Existing defenses mainly rely on Byzantine-robust FL methods, which aim to learn an accurate global model even if some clients are malicious. However, they can only resist a small number of malicious clients in practice. It is still an open challenge how to defend against model poisoning attacks with a large number of malicious clients. Our FLDetector addresses this challenge via detecting malicious clients. FLDetector aims to detect and remove the majority of the malicious clients such that a Byzantine-robust FL method can learn an accurate global model using the remaining clients. Our key observation is that, in model poisoning attacks, the model updates from a client in multiple iterations are inconsistent. Therefore, FLDetector detects malicious clients via checking their model-updates consistency. Roughly speaking, the server predicts a client's model update in each iteration based on its historical model updates using the Cauchy mean value theorem and L-BFGS, and flags a client as malicious if the received model update from the client and the predicted model update are inconsistent in multiple iterations. Our extensive experiments on three benchmark datasets show that FLDetector can accurately detect malicious clients in multiple state-of-the-art model poisoning attacks. After removing the detected malicious clients, existing Byzantine-robust FL methods can learn accurate global models.Our code is available at https://github.com/zaixizhang/FLDetector.

cs.CR↗