arXiv:2510.25132q-bio.BMcs.LG2025-10NeurIPS被引 3

让酶生成模型精准控制底物特异性,提升设计成功率与催化效率。

EnzyControl: Adding Functional and Substrate-Specific Control for Enzyme Backbone Generation

  • 基于多序列比对的催化位点与底物联合建模,实现功能与底物双约束生成。
  • 在两个基准上提升13%的设计成功率和催化效率,优于现有基线模型。
  • 轻量模块化设计,适配预训练骨架模型,适合新酶结构设计研究者使用。

设计具有底物特异性的酶骨架是计算蛋白质工程中的关键挑战。当前生成模型在结合数据、底物特异性控制和从头酶骨架生成灵活性方面存在局限。为此,我们构建了包含11,100个实验验证的酶-底物对的EnzyBind数据集,源自PDBbind并经过专门筛选。在此基础上,提出EnzyControl方法,实现酶骨架生成的功能与底物特异性控制。该方法通过自动提取经筛选的酶-底物数据中的多序列比对标注催化位点及其对应底物,作为生成条件。EnzyControl的核心是轻量级模块化组件EnzyAdapter,可嵌入预训练的基序-支架模型中,使其具备底物感知能力。采用两阶段训练策略进一步优化生成结构的准确性和功能性。实验表明,EnzyControl在EnzyBind和EnzyBench基准上均达到最优性能,相较于基线模型,在设计性上提升13%,催化效率提升13%。代码已开源于https://github.com/Vecteur-libre/EnzyControl。

原文摘要 · Abstract (English)

Designing enzyme backbones with substrate-specific functionality is a critical challenge in computational protein engineering. Current generative models excel in protein design but face limitations in binding data, substrate-specific control, and flexibility for de novo enzyme backbone generation. To address this, we introduce EnzyBind, a dataset with 11,100 experimentally validated enzyme-substrate pairs specifically curated from PDBbind. Building on this, we propose EnzyControl, a method that enables functional and substrate-specific control in enzyme backbone generation. Our approach generates enzyme backbones conditioned on MSA-annotated catalytic sites and their corresponding substrates, which are automatically extracted from curated enzyme-substrate data. At the core of EnzyControl is EnzyAdapter, a lightweight, modular component integrated into a pretrained motif-scaffolding model, allowing it to become substrate-aware. A two-stage training paradigm further refines the model's ability to generate accurate and functional enzyme structures. Experiments show that our EnzyControl achieves the best performance across structural and functional metrics on EnzyBind and EnzyBench benchmarks, with particularly notable improvements of 13\% in designability and 13\% in catalytic efficiency compared to the baseline models. The code is released at https://github.com/Vecteur-libre/EnzyControl.

酶设计生成模型底物特异性蛋白质工程

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