A significant amount of protein function requires binding small molecules, including enzymatic catalysis. As such, designing binding pockets for small molecules has several impactful applications ranging from drug synthesis to energy storage. Towards this goal, we first develop HarmonicFlow, an improved generative process over 3D protein-ligand binding structures based on our self-conditioned flow matching objective. FlowSite extends this flow model to jointly generate a protein pocket's discrete residue types and the molecule's binding 3D structure. We show that HarmonicFlow improves upon the state-of-the-art generative processes for docking in simplicity, generality, and performance. Enabled by this structure modeling, FlowSite designs binding sites substantially better than baseline approaches and provides the first general solution for binding site design.

翻译：大量蛋白质功能依赖于小分子结合，包括酶催化反应。因此，设计小分子结合口袋在药物合成到能量储存等多个领域具有重要应用价值。为实现这一目标，我们首先提出HarmonicFlow——一种基于自条件流匹配目标的改进型3D蛋白质-配体结合结构生成过程。FlowSite将该流模型扩展为能够联合生成蛋白质口袋的离散残基类型与分子的三维结合结构。研究表明：HarmonicFlow在简洁性、通用性和性能上均超越了当前最先进的对接生成过程。借助该结构建模能力，FlowSite在结合位点设计上显著优于基准方法，并首次为结合位点设计提供了通用解决方案。