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Cheng Tan

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20 papers

2 author rows

NeurIPS Conference 2025 Conference Paper

AlphaFold Database Debiasing for Robust Inverse Folding

Cheng Tan
Zhenxiao Cao
Zhangyang Gao
Siyuan Li
Yufei Huang
Stan Z. Li

The AlphaFold Protein Structure Database (AFDB) offers unparalleled structural coverage at near-experimental accuracy, positioning it as a valuable resource for data-driven protein design. However, its direct use in training deep models that are sensitive to fine-grained atomic geometry—such as inverse folding—exposes a critical limitation. Comparative analysis of structural feature distributions reveals that AFDB structures exhibit distinct statistical regularities, reflecting a systematic geometric bias that deviates from the conformational diversity found in experimentally determined structures from the Protein Data Bank (PDB). While AFDB structures are cleaner and more idealized, PDB structures capture the intrinsic variability and physical realism essential for generalization in downstream tasks. To address this discrepancy, we introduce a Debiasing Structure AutoEncoder (DeSAE) that learns to reconstruct native-like conformations from intentionally corrupted backbone geometries. By training the model to recover plausible structural states, DeSAE implicitly captures a more robust and natural structural manifold. At inference, applying DeSAE to AFDB structures produces debiased structures that significantly improve inverse folding performance across multiple benchmarks. This work highlights the critical impact of subtle systematic biases in predicted structures and presents a principled framework for debiasing, significantly boosting the performance of structure-based learning tasks like inverse folding.

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AAAI Conference 2025 Conference Paper

dyAb: Flow Matching for Flexible Antibody Design with AlphaFold-driven Pre-binding Antigen

Cheng Tan
Yijie Zhang
Zhangyang Gao
Yufei Huang
Haitao Lin
Lirong Wu
Fandi Wu
Mathieu Blanchette

The development of therapeutic antibodies heavily relies on accurate predictions of how antigens will interact with antibodies. Existing computational methods in antibody design often overlook crucial conformational changes that antigens undergo during the binding process, significantly impacting the reliability of the resulting antibodies. To bridge this gap, we introduce dyAb, a flexible framework that incorporates AlphaFold2-driven predictions to model pre-binding antigen structures and specifically addresses the dynamic nature of antigen conformation changes. Our dyAb model leverages a unique combination of coarse-grained interface alignment and fine-grained flow matching techniques to simulate the interaction dynamics and structural evolution of the antigen-antibody complex, providing a realistic representation of the binding process. Extensive experiments show that dyAb significantly outperforms existing models in antibody design involving changing antigen conformations. These results highlight dyAb's potential to streamline the design process for therapeutic antibodies, promising more efficient development cycles and improved outcomes in clinical applications.

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AAAI Conference 2025 Conference Paper

FoldToken: Learning Protein Language via Vector Quantization and Beyond

Zhangyang Gao
Cheng Tan
Jue Wang
Yufei Huang
Lirong Wu
Stan Z. Li

Is there a foreign language describing protein sequences and structures simultaneously? Protein structures, represented by continuous 3D points, have long posed a challenge due to the contrasting modeling paradigms of discrete sequences. We introduce FoldTokenizer to represent protein sequence-structure as discrete symbols. This approach involves projecting residue types and structures into a discrete space, guided by a reconstruction loss for information preservation. We name the learned discrete symbols as FoldToken, and the sequence of FoldTokens serves as a new protein language, transforming the protein sequence-structure into a unified modality. We apply the created protein language on general backbone inpainting task, building the first GPT-style model (FoldGPT) for sequence-structure co-generation with promising results. Key to our success is the substantial enhancement of the vector quantization module, Soft Conditional Vector Quantization (SoftCVQ).

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NeurIPS Conference 2025 Conference Paper

ProtInvTree: Deliberate Protein Inverse Folding with Reward-guided Tree Search

Mengdi Liu
Xiaoxue Cheng
Zhangyang Gao
Hong Chang
Cheng Tan
Shiguang Shan
Xilin Chen

Designing protein sequences that fold into a target 3D structure—known as protein inverse folding—is a fundamental challenge in protein engineering. While recent deep learning methods have achieved impressive performance by recovering native sequences, they often overlook the one-to-many nature of the problem: multiple diverse sequences can fold into the same structure. This motivates the need for a generative model capable of designing diverse sequences while preserving structural consistency. To address this trade-off, we introduce ProtInvTree, the first reward-guided tree-search framework for protein inverse folding. ProtInvTree reformulates sequence generation as a deliberate, step-wise decision-making process, enabling the exploration of multiple design paths and exploitation of promising candidates through self-evaluation, lookahead, and backtracking. We propose a two-stage focus-and-grounding action mechanism that decouples position selection and residue generation. To efficiently evaluate intermediate states, we introduce a jumpy denoising strategy that avoids full rollouts. Built upon pretrained protein language models, ProtInvTree supports flexible test-time scaling by adjusting the search depth and breadth without retraining. Empirically, ProtInvTree outperforms state-of-the-art baselines across multiple benchmarks, generating structurally consistent yet diverse sequences, including those far from the native ground truth. The code is available at https: //github. com/A4Bio/ProteinInvBench/.

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AAAI Conference 2025 Conference Paper

Relation-Aware Equivariant Graph Networks for Epitope-Unknown Antibody Design and Specificity Optimization

Lirong Wu
Haitao Lin
Yufei Huang
Zhangyang Gao
Cheng Tan
Yunfan Liu
Tailin Wu
Stan Z. Li

Antibodies are Y-shaped proteins that protect the host by binding to specific antigens, and their binding is mainly determined by the Complementary Determining Regions (CDRs) in the antibody. Despite the great progress made in CDR design, existing computational methods still encounter several challenges: 1) poor capability of modeling complex CDRs with long sequences due to insufficient contextual information; 2) conditioned on pre-given antigenic epitopes and their static interaction with the target antibody; 3) neglect of specificity during antibody optimization leads to non-specific antibodies. In this paper, we take into account a variety of node features, edge features, and edge relations to include more contextual and geometric information. We propose a novel Relation-Aware Antibody Design (RAAD) framework, which dynamically models antigen-antibody interactions for co-designing the sequences and structures of antigen-specific CDRs. Furthermore, we propose a new evaluation metric to better measure antibody specificity and develop a contrasting specificity-enhancing constraint to optimize the specificity of antibodies. Extensive experiments have demonstrated the superior capability of RAAD in terms of antibody modeling, generation, and optimization across different CDR types, sequence lengths, pre-training strategies, and input contexts.

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IJCAI Conference 2025 Conference Paper

SketchAgent: Generating Structured Diagrams from Hand-Drawn Sketches

Cheng Tan
Qi Chen
Jingxuan Wei
Gaowei Wu
Zhangyang Gao
Siyuan Li
Bihui Yu
Ruifeng Guo

Hand-drawn sketches are a natural and efficient medium for capturing and conveying ideas. Despite significant advancements in controllable natural image generation, translating freehand sketches into structured, machine-readable diagrams remains a labor-intensive and predominantly manual task. The primary challenge stems from the inherent ambiguity of sketches, which lack the structural constraints and semantic precision required for automated diagram generation. To address this challenge, we introduce SketchAgent, a multi-agent system designed to automate the transformation of hand-drawn sketches into structured diagrams. SketchAgent integrates sketch recognition, symbolic reasoning, and iterative validation to produce semantically coherent and structurally accurate diagrams, significantly reducing the need for manual effort. To evaluate the effectiveness of our approach, we propose the Sketch2Diagram Benchmark, a comprehensive dataset and evaluation framework encompassing eight diverse diagram categories, such as flowcharts, directed graphs, and model architectures. The dataset comprises over 6, 000 high-quality examples with token-level annotations, standardized preprocessing, and rigorous quality control. By streamlining the diagram generation process, SketchAgent holds great promise for applications in design, education, and engineering, while offering a significant step toward bridging the gap between intuitive sketching and machine-readable diagram generation.

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NeurIPS Conference 2024 Conference Paper

AdaNovo: Towards Robust \emph{De Novo} Peptide Sequencing in Proteomics against Data Biases

Jun Xia
Shaorong Chen
Jingbo Zhou
Xiaojun Shan
Wenjie Du
Zhangyang Gao
Cheng Tan
Bozhen Hu

Tandem mass spectrometry has played a pivotal role in advancing proteomics, enabling the high-throughput analysis of protein composition in biological tissues. Despite the development of several deep learning methods for predicting amino acid sequences (peptides) responsible for generating the observed mass spectra, training data biases hinder further advancements of \emph{de novo} peptide sequencing. Firstly, prior methods struggle to identify amino acids with Post-Translational Modifications (PTMs) due to their lower frequency in training data compared to canonical amino acids, further resulting in unsatisfactory peptide sequencing performance. Secondly, various noise and missing peaks in mass spectra reduce the reliability of training data (Peptide-Spectrum Matches, PSMs). To address these challenges, we propose AdaNovo, a novel and domain knowledge-inspired framework that calculates Conditional Mutual Information (CMI) between the mass spectra and amino acids or peptides, using CMI for robust training against above biases. Extensive experiments indicate that AdaNovo outperforms previous competitors on the widely-used 9-species benchmark, meanwhile yielding 3. 6\% - 9. 4\% improvements in PTMs identification. The supplements contain the code.

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AAAI Conference 2024 Conference Paper

Cross-Gate MLP with Protein Complex Invariant Embedding Is a One-Shot Antibody Designer

Cheng Tan
Zhangyang Gao
Lirong Wu
Jun Xia
Jiangbin Zheng
Xihong Yang
Yue Liu
Bozhen Hu

Antibodies are crucial proteins produced by the immune system in response to foreign substances or antigens. The specificity of an antibody is determined by its complementarity-determining regions (CDRs), which are located in the variable domains of the antibody chains and form the antigen-binding site. Previous studies have utilized complex techniques to generate CDRs, but they suffer from inadequate geometric modeling. Moreover, the common iterative refinement strategies lead to an inefficient inference. In this paper, we propose a simple yet effective model that can co-design 1D sequences and 3D structures of CDRs in a one-shot manner. To achieve this, we decouple the antibody CDR design problem into two stages: (i) geometric modeling of protein complex structures and (ii) sequence-structure co-learning. We develop a novel macromolecular structure invariant embedding, typically for protein complexes, that captures both intra- and inter-component interactions among the backbone atoms, including Calpha, N, C, and O atoms, to achieve comprehensive geometric modeling. Then, we introduce a simple cross-gate MLP for sequence-structure co-learning, allowing sequence and structure representations to implicitly refine each other. This enables our model to design desired sequences and structures in a one-shot manner. Extensive experiments are conducted to evaluate our results at both the sequence and structure level, which demonstrate that our model achieves superior performance compared to the state-of-the-art antibody CDR design methods.

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NeurIPS Conference 2024 Conference Paper

FlexMol: A Flexible Toolkit for Benchmarking Molecular Relational Learning

Sizhe Liu
Jun Xia
Lecheng Zhang
Yuchen Liu
Yue Liu
Wenjie Du
Zhangyang Gao
Bozhen Hu

Molecular relational learning (MRL) is crucial for understanding the interaction behaviors between molecular pairs, a critical aspect of drug discovery and development. However, the large feasible model space of MRL poses significant challenges to benchmarking, and existing MRL frameworks face limitations in flexibility and scope. To address these challenges, avoid repetitive coding efforts, and ensure fair comparison of models, we introduce FlexMol, a comprehensive toolkit designed to facilitate the construction and evaluation of diverse model architectures across various datasets and performance metrics. FlexMol offers a robust suite of preset model components, including 16 drug encoders, 13 protein sequence encoders, 9 protein structure encoders, and 7 interaction layers. With its easy-to-use API and flexibility, FlexMol supports the dynamic construction of over 70, 000 distinct combinations of model architectures. Additionally, we provide detailed benchmark results and code examples to demonstrate FlexMol’s effectiveness in simplifying and standardizing MRL model development and comparison. FlexMol is open-sourced and available at https: //github. com/Steven51516/FlexMol.

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NeurIPS Conference 2024 Conference Paper

Learning Complete Protein Representation by Dynamically Coupling of Sequence and Structure

Bozhen Hu
Cheng Tan
Jun Xia
Yue Liu
Lirong Wu
Jiangbin Zheng
Yongjie Xu
Yufei Huang

Learning effective representations is imperative for comprehending proteins and deciphering their biological functions. Recent strides in language models and graph neural networks have empowered protein models to harness primary or tertiary structure information for representation learning. Nevertheless, the absence of practical methodologies to appropriately model intricate inter-dependencies between protein sequences and structures has resulted in embeddings that exhibit low performance on tasks such as protein function prediction. In this study, we introduce CoupleNet, a novel framework designed to interlink protein sequences and structures to derive informative protein representations. CoupleNet integrates multiple levels and scales of features in proteins, encompassing residue identities and positions for sequences, as well as geometric representations for tertiary structures from both local and global perspectives. A two-type dynamic graph is constructed to capture adjacent and distant sequential features and structural geometries, achieving completeness at the amino acid and backbone levels. Additionally, convolutions are executed on nodes and edges simultaneously to generate comprehensive protein embeddings. Experimental results on benchmark datasets showcase that CoupleNet outperforms state-of-the-art methods, exhibiting particularly superior performance in low-sequence similarities scenarios, adeptly identifying infrequently encountered functions and effectively capturing remote homology relationships in proteins.

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NeurIPS Conference 2024 Conference Paper

NN4SysBench: Characterizing Neural Network Verification for Computer Systems

Shuyi Lin
Haoyu He
Tianhao Wei
Kaidi Xu
Huan ZHang
Gagandeep Singh
Changliu Liu
Cheng Tan

We present NN4SysBench, a benchmark suite for neural network verification that is composed of applications from the domain of computer systems. We call these neural networks for computer systems or NN4Sys. NN4Sys is booming: there are many proposals for using neural networks in computer systems—for example, databases, OSes, and networked systems—many of which are safety critical. Neural network verification is a technique to formally verify whether neural networks satisfy safety properties. We however observe that NN4Sys has some unique characteristics that today’s verification tools overlook and have limited support. Therefore, this benchmark suite aims at bridging the gap between NN4Sys and the verification by using impactful NN4Sys applications as benchmarks to illustrate computer systems’ unique challenges. We also build a compatible version of NN4SysBench, so that today’s verifiers can also work on these benchmarks with approximately the same verification difficulties. The code is available at https: //github. com/lydialin1212/NN4Sys_Benchmark.

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NeurIPS Conference 2024 Conference Paper

ProtGO: Function-Guided Protein Modeling for Unified Representation Learning

Bozhen Hu
Cheng Tan
Yongjie Xu
Zhangyang Gao
Jun Xia
Lirong Wu
Stan Z. Li

Protein representation learning is indispensable for various downstream applications of artificial intelligence for bio-medicine research, such as drug design and function prediction. However, achieving effective representation learning for proteins poses challenges due to the diversity of data modalities involved, including sequence, structure, and function annotations. Despite the impressive capabilities of large language models in biomedical text modelling, there remains a pressing need for a framework that seamlessly integrates these diverse modalities, particularly focusing on the three critical aspects of protein information: sequence, structure, and function. Moreover, addressing the inherent data scale differences among these modalities is essential. To tackle these challenges, we introduce ProtGO, a unified model that harnesses a teacher network equipped with a customized graph neural network (GNN) and a Gene Ontology (GO) encoder to learn hybrid embeddings. Notably, our approach eliminates the need for additional functions as input for the student network, which shares the same GNN module. Importantly, we utilize a domain adaptation method to facilitate distribution approximation for guiding the training of the teacher-student framework. This approach leverages distributions learned from latent representations to avoid the alignment of individual samples. Benchmark experiments highlight that ProtGO significantly outperforms state-of-the-art baselines, clearly demonstrating the advantages of the proposed unified framework.

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AAAI Conference 2024 Conference Paper

PSC-CPI: Multi-Scale Protein Sequence-Structure Contrasting for Efficient and Generalizable Compound-Protein Interaction Prediction

Lirong Wu
Yufei Huang
Cheng Tan
Zhangyang Gao
Bozhen Hu
Haitao Lin
Zicheng Liu
Stan Z. Li

Compound-Protein Interaction (CPI) prediction aims to predict the pattern and strength of compound-protein interactions for rational drug discovery. Existing deep learning-based methods utilize only the single modality of protein sequences or structures and lack the co-modeling of the joint distribution of the two modalities, which may lead to significant performance drops in complex real-world scenarios due to various factors, e.g., modality missing and domain shifting. More importantly, these methods only model protein sequences and structures at a single fixed scale, neglecting more fine-grained multi-scale information, such as those embedded in key protein fragments. In this paper, we propose a novel multi-scale Protein Sequence-structure Contrasting framework for CPI prediction (PSC-CPI), which captures the dependencies between protein sequences and structures through both intra-modality and cross-modality contrasting. We further apply length-variable protein augmentation to allow contrasting to be performed at different scales, from the amino acid level to the sequence level. Finally, in order to more fairly evaluate the model generalizability, we split the test data into four settings based on whether compounds and proteins have been observed during the training stage. Extensive experiments have shown that PSC-CPI generalizes well in all four settings, particularly in the more challenging ``Unseen-Both" setting, where neither compounds nor proteins have been observed during training. Furthermore, even when encountering a situation of modality missing, i.e., inference with only single-modality protein data, PSC-CPI still exhibits comparable or even better performance than previous approaches.

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NeurIPS Conference 2024 Conference Paper

UniIF: Unified Molecule Inverse Folding

Zhangyang Gao
Jue Wang
Cheng Tan
Lirong Wu
Yufei Huang
Siyuan Li
Zhirui Ye
Stan Z. Li

Molecule inverse folding has been a long-standing challenge in chemistry and biology, with the potential to revolutionize drug discovery and material science. Despite specified models have been proposed for different small- or macro-molecules, few have attempted to unify the learning process, resulting in redundant efforts. Complementary to recent advancements in molecular structure prediction, such as RoseTTAFold All-Atom and AlphaFold3, we propose the unified model UniIF for the inverse folding of all molecules. We do such unification in two levels: 1) Data-Level: We propose a unified block graph data form for all molecules, including the local frame building and geometric feature initialization. 2) Model-Level: We introduce a geometric block attention network, comprising a geometric interaction, interactive attention and virtual long-term dependency modules, to capture the 3D interactions of all molecules. Through comprehensive evaluations across various tasks such as protein design, RNA design, and material design, we demonstrate that our proposed method surpasses state-of-the-art methods on all tasks. UniIF offers a versatile and effective solution for general molecule inverse folding.

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AAAI Conference 2024 Conference Paper

Wavelet-Driven Spatiotemporal Predictive Learning: Bridging Frequency and Time Variations

Xuesong Nie
Yunfeng Yan
Siyuan Li
Cheng Tan
Xi Chen
Haoyuan Jin
Zhihang Zhu
Stan Z. Li

Spatiotemporal predictive learning is a paradigm that empowers models to learn spatial and temporal patterns by predicting future frames from past frames in an unsupervised manner. This method typically uses recurrent units to capture long-term dependencies, but these units often come with high computational costs and limited performance in real-world scenes. This paper presents an innovative Wavelet-based SpatioTemporal (WaST) framework, which extracts and adaptively controls both low and high-frequency components at image and feature levels via 3D discrete wavelet transform for faster processing while maintaining high-quality predictions. We propose a Time-Frequency Aware Translator uniquely crafted to efficiently learn short- and long-range spatiotemporal information by individually modeling spatial frequency and temporal variations. Meanwhile, we design a wavelet-domain High-Frequency Focal Loss that effectively supervises high-frequency variations. Extensive experiments across various real-world scenarios, such as driving scene prediction, traffic flow prediction, human motion capture, and weather forecasting, demonstrate that our proposed WaST achieves state-of-the-art performance over various spatiotemporal prediction methods.

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NeurIPS Conference 2023 Conference Paper

Harnessing Hard Mixed Samples with Decoupled Regularizer

Zicheng Liu
Siyuan Li
Ge Wang
Lirong Wu
Cheng Tan
Stan Z. Li

Mixup is an efficient data augmentation approach that improves the generalization of neural networks by smoothing the decision boundary with mixed data. Recently, dynamic mixup methods have improved previous \textit{static} policies effectively (e. g. , linear interpolation) by maximizing target-related salient regions in mixed samples, but excessive additional time costs are not acceptable. These additional computational overheads mainly come from optimizing the mixed samples according to the mixed labels. However, we found that the extra optimizing step may be redundant because label-mismatched mixed samples are informative hard mixed samples for deep models to localize discriminative features. In this paper, we thus are not trying to propose a more complicated dynamic mixup policy but rather an efficient mixup objective function with decoupled regularizer, named decoupled mixup (DM). The primary effect is that DM can adaptively utilize those hard mixed samples to mine discriminative features without losing the original smoothness of mixup. As a result, DM enables static mixup methods to achieve comparable or even exceed the performance of dynamic methods without any extra computation. This also leads to an interesting objective design problem for mixup training that we need to focus on both smoothing the decision boundaries and identifying discriminative features. Extensive experiments on supervised and semi-supervised learning benchmarks across seven datasets validate the effectiveness of DM.

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NeurIPS Conference 2023 Conference Paper

OpenSTL: A Comprehensive Benchmark of Spatio-Temporal Predictive Learning

Cheng Tan
Siyuan Li
Zhangyang Gao
Wenfei Guan
Zedong Wang
Zicheng Liu
Lirong Wu
Stan Z. Li

Spatio-temporal predictive learning is a learning paradigm that enables models to learn spatial and temporal patterns by predicting future frames from given past frames in an unsupervised manner. Despite remarkable progress in recent years, a lack of systematic understanding persists due to the diverse settings, complex implementation, and difficult reproducibility. Without standardization, comparisons can be unfair and insights inconclusive. To address this dilemma, we propose OpenSTL, a comprehensive benchmark for spatio-temporal predictive learning that categorizes prevalent approaches into recurrent-based and recurrent-free models. OpenSTL provides a modular and extensible framework implementing various state-of-the-art methods. We conduct standard evaluations on datasets across various domains, including synthetic moving object trajectory, human motion, driving scenes, traffic flow, and weather forecasting. Based on our observations, we provide a detailed analysis of how model architecture and dataset properties affect spatio-temporal predictive learning performance. Surprisingly, we find that recurrent-free models achieve a good balance between efficiency and performance than recurrent models. Thus, we further extend the common MetaFormers to boost recurrent-free spatial-temporal predictive learning. We open-source the code and models at https: //github. com/chengtan9907/OpenSTL.

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ICLR Conference 2023 Conference Paper

Personalized Reward Learning with Interaction-Grounded Learning (IGL)

Jessica Maghakian
Paul Mineiro
Kishan Panaganti
Mark Rucker
Akanksha Saran
Cheng Tan

In an era of countless content offerings, recommender systems alleviate information overload by providing users with personalized content suggestions. Due to the scarcity of explicit user feedback, modern recommender systems typically optimize for the same fixed combination of implicit feedback signals across all users. However, this approach disregards a growing body of work highlighting that (i) implicit signals can be used by users in diverse ways, signaling anything from satisfaction to active dislike, and (ii) different users communicate preferences in different ways. We propose applying the recent Interaction Grounded Learning (IGL) paradigm to address the challenge of learning representations of diverse user communication modalities. Rather than requiring a fixed, human-designed reward function, IGL is able to learn personalized reward functions for different users and then optimize directly for the latent user satisfaction. We demonstrate the success of IGL with experiments using simulations as well as with real-world production traces.

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NeurIPS Conference 2023 Conference Paper

ProteinInvBench: Benchmarking Protein Inverse Folding on Diverse Tasks, Models, and Metrics

Zhangyang Gao
Cheng Tan
Yijie Zhang
Xingran Chen
Lirong Wu
Stan Z. Li

Protein inverse folding has attracted increasing attention in recent years. However, we observe that current methods are usually limited to the CATH dataset and the recovery metric. The lack of a unified framework for ensembling and comparing different methods hinders the comprehensive investigation. In this paper, we propose ProteinBench, a new benchmark for protein design, which comprises extended protein design tasks, integrated models, and diverse evaluation metrics. We broaden the application of methods originally designed for single-chain protein design to new scenarios of multi-chain and \textit{de novo} protein design. Recent impressive methods, including GraphTrans, StructGNN, GVP, GCA, AlphaDesign, ProteinMPNN, PiFold and KWDesign are integrated into our framework. In addition to the recovery, we also evaluate the confidence, diversity, sc-TM, efficiency, and robustness to thoroughly revisit current protein design approaches and inspire future work. As a result, we establish the first comprehensive benchmark for protein design, which is publicly available at \url{https: //github. com/A4Bio/OpenCPD}.

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NeurIPS Conference 2023 Conference Paper

Understanding the Limitations of Deep Models for Molecular property prediction: Insights and Solutions

Jun Xia
Lecheng Zhang
Xiao Zhu
Yue Liu
Zhangyang Gao
Bozhen Hu
Cheng Tan
Jiangbin Zheng

Molecular Property Prediction (MPP) is a crucial task in the AI-driven Drug Discovery (AIDD) pipeline, which has recently gained considerable attention thanks to advancements in deep learning. However, recent research has revealed that deep models struggle to beat traditional non-deep ones on MPP. In this study, we benchmark 12 representative models (3 non-deep models and 9 deep models) on 15 molecule datasets. Through the most comprehensive study to date, we make the following key observations: \textbf{(\romannumeral 1)} Deep models are generally unable to outperform non-deep ones; \textbf{(\romannumeral 2)} The failure of deep models on MPP cannot be solely attributed to the small size of molecular datasets; \textbf{(\romannumeral 3)} In particular, some traditional models including XGB and RF that use molecular fingerprints as inputs tend to perform better than other competitors. Furthermore, we conduct extensive empirical investigations into the unique patterns of molecule data and inductive biases of various models underlying these phenomena. These findings stimulate us to develop a simple-yet-effective feature mapping method for molecule data prior to feeding them into deep models. Empirically, deep models equipped with this mapping method can beat non-deep ones in most MoleculeNet datasets. Notably, the effectiveness is further corroborated by extensive experiments on cutting-edge dataset related to COVID-19 and activity cliff datasets.

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