发表机构
University of Connecticut（康涅狄格大学）
机构由 AI 辅助整理，请以论文原文为准。AI 中文总结
PocketVE提出一种结合稳定坐标去噪与推理时性质引导的方差爆炸扩散框架，在CrossDocked2020上显著提升三维有效性并降低应变能，实现稳定与性质引导的耦合设计。
AI 中文摘要
蛋白质条件的三维分子生成是基于结构的药物设计中的核心挑战，需要在口袋兼容性、分子性质和物理几何之间取得平衡。我们提出了PocketVE，一种蛋白质口袋条件的方差爆炸（VE）扩散框架，该框架将稳定的坐标去噪与推理时性质引导相结合。具体而言，PocketVE结合了用于三维去噪的EDM式训练和采样设置、无需外部性质分类器的多性质引导的分类器自由引导，以及作为训练时口袋正则化器的自适应蛋白质扰动。在GenBench3D协议下的CrossDocked2020上评估时，相对于其TAGMol架构基线，PocketVE将Valid$_{3\ ext{D}}$从58.6提高到80.6，并将应变能从457.4降低到127.9，同时在中等引导下保持了有竞争力的对接和分子性质得分。引导尺度研究表明，中等引导在目标相关目标和几何质量之间提供了有利的平衡，而更强的引导可能会降低几何和分布保真度。口袋置换和PoseCheck诊断进一步支持了口袋特异性空间兼容性并减少了空间冲突。总体而言，结果表明几何稳定性和推理时性质引导应被视为耦合的设计目标。
英文摘要
Protein-conditioned 3D molecule generation is a central challenge in structure-based drug design, requiring a balance between pocket compatibility, molecular properties, and physical geometry. We propose \textbf{PocketVE}, a protein-pocket-conditioned variance-exploding (VE) diffusion framework that couples stable coordinate denoising with inference-time property guidance. Specifically, PocketVE combines an EDM-style training and sampling setup for 3D denoising, classifier-free guidance for multi-property steering, and adaptive protein perturbation as a training-time pocket regularizer.On the CrossDocked2020 benchmark under GenBench3D, PocketVE improves Valid$_{3\text{D}}$ from 58.6 to 80.6 and reduces strain energy from 457.4 to 127.9 relative to its guided TAGMol architectural parent; relative to TargetDiff, it attains comparable Valid$_{3\text{D}}$ with lower strain energy (127.9 vs.\ 306.0), while retaining competitive docking and molecular-property scores under moderate guidance. A guidance-scale study shows that moderate guidance gives a favorable balance between target-related objectives and geometric quality, whereas stronger guidance can degrade geometry and distributional fidelity. Pocket-permutation and PoseCheck diagnostics further support pocket-specific spatial compatibility with reduced steric conflicts. Overall, the results suggest that geometric stability and inference-time property guidance should be considered as coupled design objectives.
CommentsAccepted by Neurips 2026
