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Zhifeng Gao

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9 papers

2 author rows

ICLR Conference 2025 Conference Paper

A Simple yet Effective ΔΔG Predictor is An Unsupervised Antibody Optimizer and Explainer

Lirong Wu
Yunfan Liu 0002
Haitao Lin
Yufei Huang 0002
Guojiang Zhao
Zhifeng Gao
Stan Z. Li

The proteins that exist today have been optimized over billions of years of natural evolution, during which nature creates random mutations and selects them. The discovery of functionally promising mutations is challenged by the limited evolutionary accessible regions, i.e., only a small region on the fitness landscape is beneficial. There have been numerous priors used to constrain protein evolution to regions of landscapes with high-fitness variants, among which the change in binding free energy ($\Delta\Delta G$) of protein complexes upon mutations is one of the most commonly used priors. However, the huge mutation space poses two challenges: (1) how to improve the efficiency of $\Delta\Delta G$ prediction for fast mutation screening; and (2) how to explain mutation preferences and efficiently explore accessible evolutionary regions. To address these challenges, we propose a lightweight $\Delta\Delta G$ predictor (Light-DDG), which adopts a structure-aware Transformer as the backbone and enhances it by knowledge distilled from existing powerful but computationally heavy $\Delta\Delta G$ predictors. Additionally, we augmented, annotated, and released a large-scale dataset containing millions of mutation data for pre-training Light-DDG. We find that such a simple yet effective Light-DDG can serve as a good unsupervised antibody optimizer and explainer. For the target antibody, we propose a novel Mutation Explainer to learn mutation preferences, which accounts for the marginal benefit of each mutation per residue. To further explore accessible evolutionary regions, we conduct preference-guided antibody optimization and evaluate antibody candidates quickly using Light-DDG to identify desirable mutations. Extensive experiments have demonstrated the effectiveness of Light-DDG in terms of test generalizability, noise robustness, and inference practicality, e.g., 89.7$\times$ inference acceleration and 15.45\% performance gains over previous state-of-the-art baselines. A case study of SARS-CoV-2 further demonstrates the crucial role of Light-DDG for mutation explanation and antibody optimization.

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ICML Conference 2025 Conference Paper

Beyond Atoms: Enhancing Molecular Pretrained Representations with 3D Space Modeling

Shuqi Lu
Xiaohong Ji
Bohang Zhang
Lin Yao 0003
Siyuan Liu
Zhifeng Gao
Linfeng Zhang 0002
Guolin Ke

Molecular pretrained representations (MPR) has emerged as a powerful approach for addressing the challenge of limited supervised data in applications such as drug discovery and material design. While early MPR methods relied on 1D sequences and 2D graphs, recent advancements have incorporated 3D conformational information to capture rich atomic interactions. However, these prior models treat molecules merely as discrete atom sets, overlooking the space surrounding them. We argue from a physical perspective that only modeling these discrete points is insufficient. We first present a simple yet insightful observation: naively adding randomly sampled virtual points beyond atoms can surprisingly enhance MPR performance. In light of this, we propose a principled framework that incorporates the entire 3D space spanned by molecules. We implement the framework via a novel Transformer-based architecture, dubbed SpaceFormer, with three key components: (1)grid-based space discretization; (2)grid sampling/merging; and (3)efficient 3D positional encoding. Extensive experiments show that SpaceFormer significantly outperforms previous 3D MPR models across various downstream tasks with limited data, validating the benefit of leveraging the additional 3D space beyond atoms in MPR models.

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ICLR Conference 2025 Conference Paper

CBGBench: Fill in the Blank of Protein-Molecule Complex Binding Graph

Haitao Lin
Guojiang Zhao
Odin Zhang
Yufei Huang 0002
Lirong Wu
Cheng Tan 0012
Zicheng Liu 0006
Zhifeng Gao

Structure-based drug design (SBDD) aims to generate potential drugs that can bind to a target protein and is greatly expedited by the aid of AI techniques in generative models. However, a lack of systematic understanding persists due to the diverse settings, complex implementation, difficult reproducibility, and task singularity. Firstly, the absence of standardization can lead to unfair comparisons and inconclusive insights. To address this dilemma, we propose CBGBench, a comprehensive benchmark for SBDD, that unifies the task as a generative graph completion, analogous to fill-in-the-blank of the 3D complex binding graph. By categorizing existing methods based on their attributes, CBGBench facilitates a modular and extensible framework that implements cutting-edge methods. Secondly, a single de novo molecule generation task can hardly reflect their capabilities. To broaden the scope, we adapt these models to a range of tasks essential in drug design, considered sub-tasks within the graph fill-in-the-blank tasks. These tasks include the generative designation of de novo molecules, linkers, fragments, scaffolds, and sidechains, all conditioned on the structures of protein pockets. Our evaluations are conducted with fairness, encompassing comprehensive perspectives on interaction, chemical properties, geometry authenticity, and substructure validity. We further provide insights with analysis from empirical studies. Our results indicate that there is potential for further improvements on many tasks, with optimization in network architectures, and effective incorporation of chemical prior knowledge. Finally, to lower the barrier to entry and facilitate further developments in the field, we also provide a single [codebase](https://github.com/EDAPINENUT/CBGBench) that unifies the discussed models, data pre-processing, training, sampling, and evaluation.

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ICML Conference 2025 Conference Paper

PolyConf: Unlocking Polymer Conformation Generation through Hierarchical Generative Models

Fanmeng Wang
Wentao Guo 0004
Qi Ou
Hongshuai Wang
Haitao Lin
Hongteng Xu
Zhifeng Gao

Polymer conformation generation is a critical task that enables atomic-level studies of diverse polymer materials. While significant advances have been made in designing conformation generation methods for small molecules and proteins, these methods struggle to generate polymer conformations due to their unique structural characteristics. Meanwhile, the scarcity of polymer conformation datasets further limits progress, making this important area largely unexplored. In this work, we propose PolyConf, a pioneering tailored polymer conformation generation method that leverages hierarchical generative models to unlock new possibilities. Specifically, we decompose the polymer conformation into a series of local conformations (i. e. , the conformations of its repeating units), generating these local conformations through an autoregressive model, and then generating their orientation transformations via a diffusion model to assemble them into the complete polymer conformation. Moreover, we develop the first benchmark with a high-quality polymer conformation dataset derived from molecular dynamics simulations to boost related research in this area. The comprehensive evaluation demonstrates that PolyConf consistently outperforms existing conformation generation methods, thus facilitating advancements in polymer modeling and simulation. The whole work is available at https: //polyconf-icml25. github. io.

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NeurIPS Conference 2024 Conference Paper

Exploring Molecular Pretraining Model at Scale

Xiaohong Ji
Zhen Wang
Zhifeng Gao
Hang Zheng
Linfeng Zhang
Guolin Ke
Weinan E

In recent years, pretraining models have made significant advancements in the fields of natural language processing (NLP), computer vision (CV), and life sciences. The significant advancements in NLP and CV are predominantly driven by the expansion of model parameters and data size, a phenomenon now recognized as the scaling laws. However, research exploring scaling law in molecular pretraining model remains unexplored. In this work, we present an innovative molecular pretraining model that leverages a two-track transformer to effectively integrate features at the atomic level, graph level, and geometry structure level. Along with this, we systematically investigate the scaling law within molecular pretraining models, examining the power-law correlations between validation loss and model size, dataset size, and computational resources. Consequently, we successfully scale the model to 1. 1 billion parameters through pretraining on 800 million conformations, making it the largest molecular pretraining model to date. Extensive experiments show the consistent improvement on the downstream tasks as the model size grows up. The model with 1. 1 billion parameters also outperform over existing methods, achieving an average 27\% improvement on the QM9 and 14\% on COMPAS-1D dataset.

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NeurIPS Conference 2024 Conference Paper

S-MolSearch: 3D Semi-supervised Contrastive Learning for Bioactive Molecule Search

Gengmo Zhou
Zhen Wang
Feng Yu
Guolin Ke
Zhewei Wei
Zhifeng Gao

Virtual Screening is an essential technique in the early phases of drug discovery, aimed at identifying promising drug candidates from vast molecular libraries. Recently, ligand-based virtual screening has garnered significant attention due to its efficacy in conducting extensive database screenings without relying on specific protein-binding site information. Obtaining binding affinity data for complexes is highly expensive, resulting in a limited amount of available data that covers a relatively small chemical space. Moreover, these datasets contain a significant amount of inconsistent noise. It is challenging to identify an inductive bias that consistently maintains the integrity of molecular activity during data augmentation. To tackle these challenges, we propose S-MolSearch, the first framework to our knowledge, that leverages molecular 3D information and affinity information in semi-supervised contrastive learning for ligand-based virtual screening. % S-MolSearch processes both labeled and unlabeled data, trains molecular structural encoders, and generates soft labels for unlabeled data, drawing on the principles of inverse optimal transport. Drawing on the principles of inverse optimal transport, S-MolSearch efficiently processes both labeled and unlabeled data, training molecular structural encoders while generating soft labels for the unlabeled data. This design allows S-MolSearch to adaptively utilize unlabeled data within the learning process. Empirically, S-MolSearch demonstrates superior performance on widely-used benchmarks LIT-PCBA and DUD-E. It surpasses both structure-based and ligand-based virtual screening methods for AUROC, BEDROC and EF.

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ICLR Conference 2023 Conference Paper

Uni-Mol: A Universal 3D Molecular Representation Learning Framework

Gengmo Zhou
Zhifeng Gao
Qiankun Ding
Hang Zheng
Hongteng Xu
Zhewei Wei
Linfeng Zhang 0002
Guolin Ke

Molecular representation learning (MRL) has gained tremendous attention due to its critical role in learning from limited supervised data for applications like drug design. In most MRL methods, molecules are treated as 1D sequential tokens or 2D topology graphs, limiting their ability to incorporate 3D information for downstream tasks and, in particular, making it almost impossible for 3D geometry prediction/generation. In this paper, we propose a universal 3D MRL framework, called Uni-Mol, that significantly enlarges the representation ability and application scope of MRL schemes. Uni-Mol contains two pretrained models with the same SE(3) Transformer architecture: a molecular model pretrained by 209M molecular conformations; a pocket model pretrained by 3M candidate protein pocket data. Besides, Uni-Mol contains several finetuning strategies to apply the pretrained models to various downstream tasks. By properly incorporating 3D information, Uni-Mol outperforms SOTA in 14/15 molecular property prediction tasks. Moreover, Uni-Mol achieves superior performance in 3D spatial tasks, including protein-ligand binding pose prediction, molecular conformation generation, etc. The code, model, and data are made publicly available at https://github.com/dptech-corp/Uni-Mol.

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ICML Conference 2018 Conference Paper

PredRNN++: Towards A Resolution of the Deep-in-Time Dilemma in Spatiotemporal Predictive Learning

Yunbo Wang
Zhifeng Gao
Mingsheng Long
Jianmin Wang 0001
Philip S. Yu

We present PredRNN++, a recurrent network for spatiotemporal predictive learning. In pursuit of a great modeling capability for short-term video dynamics, we make our network deeper in time by leveraging a new recurrent structure named Causal LSTM with cascaded dual memories. To alleviate the gradient propagation difficulties in deep predictive models, we propose a Gradient Highway Unit, which provides alternative quick routes for the gradient flows from outputs back to long-range previous inputs. The gradient highway units work seamlessly with the causal LSTMs, enabling our model to capture the short-term and the long-term video dependencies adaptively. Our model achieves state-of-the-art prediction results on both synthetic and real video datasets, showing its power in modeling entangled motions.

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NeurIPS Conference 2017 Conference Paper

PredRNN: Recurrent Neural Networks for Predictive Learning using Spatiotemporal LSTMs

Yunbo Wang
Mingsheng Long
Jianmin Wang
Zhifeng Gao
Philip Yu

The predictive learning of spatiotemporal sequences aims to generate future images by learning from the historical frames, where spatial appearances and temporal variations are two crucial structures. This paper models these structures by presenting a predictive recurrent neural network (PredRNN). This architecture is enlightened by the idea that spatiotemporal predictive learning should memorize both spatial appearances and temporal variations in a unified memory pool. Concretely, memory states are no longer constrained inside each LSTM unit. Instead, they are allowed to zigzag in two directions: across stacked RNN layers vertically and through all RNN states horizontally. The core of this network is a new Spatiotemporal LSTM (ST-LSTM) unit that extracts and memorizes spatial and temporal representations simultaneously. PredRNN achieves the state-of-the-art prediction performance on three video prediction datasets and is a more general framework, that can be easily extended to other predictive learning tasks by integrating with other architectures.

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