用黎曼几何优化抗菌肽搜索,提升发现效率与活性。
PepCompass: Navigating peptide embedding spaces using Riemannian Geometry
- 构建解码器驱动的黎曼流形,捕捉局部结构并保证计算稳定。
- 提出两种局部探索方法,实现高效活性优化,发现25种广谱活性肽。
- 适合药物设计、生成模型与分子优化方向的研究者参考。
抗菌肽发现面临肽空间巨大而有效肽稀少的挑战。生成模型提供连续的潜在空间映射,但传统方法忽略解码器引起的几何结构,依赖平坦的欧几里得度量,导致探索与优化扭曲低效。先前基于流形的方法假设固有维度不变,实际中严重失效。本文提出PepCompass,一种几何感知的肽探索与优化框架。核心是定义一组$κ$-稳定黎曼流形$M^κ$,捕获局部几何并确保计算稳定性。提出两种局部探索方法:二阶黎曼布朗高效采样,提供黎曼布朗运动的收敛二阶逼近;切空间突变枚举,将切方向重新解释为氨基酸替换。二者结合形成局部枚举贝叶斯优化(LE-BO),实现高效局部活性优化。最后引入势能最小化测地线搜索(PoGS),沿属性丰富的测地线在原型嵌入间插值,引导发现向高活性种子偏移。体外验证表明,PoGS成功产出4个新种子,后续使用LE-BO优化获得25种高活性肽,对耐药菌株具广谱抑制效果。结果证明,几何感知探索为抗菌肽设计提供了强大新范式。
原文摘要 · Abstract (English)
Antimicrobial peptide discovery is challenged by the astronomical size of peptide space and the relative scarcity of active peptides. Generative models provide continuous latent "maps" of peptide space, but conventionally ignore decoder-induced geometry and rely on flat Euclidean metrics, rendering exploration and optimization distorted and inefficient. Prior manifold-based remedies assume fixed intrinsic dimensionality, which critically fails in practice for peptide data. Here, we introduce PepCompass, a geometry-aware framework for peptide exploration and optimization. At its core, we define a Union of $κ$-Stable Riemannian Manifolds $\mathbb{M}^κ$, a family of decoder-induced manifolds that captures local geometry while ensuring computational stability. We propose two local exploration methods: Second-Order Riemannian Brownian Efficient Sampling, which provides a convergent second-order approximation to Riemannian Brownian motion, and Mutation Enumeration in Tangent Space, which reinterprets tangent directions as discrete amino-acid substitutions. Combining these yields Local Enumeration Bayesian Optimization (LE-BO), an efficient algorithm for local activity optimization. Finally, we introduce Potential-minimizing Geodesic Search (PoGS), which interpolates between prototype embeddings along property-enriched geodesics, biasing discovery toward seeds, i.e. peptides with favorable activity. In-vitro validation confirms the effectiveness of PepCompass: PoGS yields four novel seeds, and subsequent optimization with LE-BO discovers 25 highly active peptides with broad-spectrum activity, including against resistant bacterial strains. These results demonstrate that geometry-informed exploration provides a powerful new paradigm for antimicrobial peptide design.
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