Protein pocket detection via convex hull surface evolution and associated Reeb graph
Protein pocket detection via convex hull surface evolution and associated Reeb graph
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DOI：
10.1093/bioinformatics/bty598
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发表时间：
2018-09
期刊：
影响因子：
5.8
通讯作者：
Rundong Zhao;Zixuan Cang;Y. Tong;G. Wei
中科院分区：
文献类型：
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作者：
Rundong Zhao;Zixuan Cang;Y. Tong;G. Wei
激励蛋白口袋信息对于药物靶标识别、激动剂设计、虚拟筛选和受体-配体结合分析具有非常重要的意义。最近的一项研究表明，大约一半的全蛋白可以同时结合包含结构化子口袋的大口袋中的多个相互作用的配体。尽管这种层次化的口袋和子口袋结构对蛋白质结合部位的多配体协同作用有显著影响，但目前还没有可用的方法来进行这种分析。本文介绍了一种基于微分几何、代数拓扑和基于物理的模拟的计算工具来解决这一紧迫的问题。结果我们提出了通过向内进化凸壳表面直到它遍及蛋白质表面来检测蛋白质凹坑的方法。控制偏微分方程组(PDE)包括平均曲率流和欧拉表示的快速行进算法中常用的eikonal方程。利用表面演化诱导Morse函数和Reeb图可控细节地刻画了分层口袋和子口袋结构。在4414个蛋白质-配体复合体的PDBind精化集上对该方法进行了验证。大量的数值试验表明，该方法不仅对口袋-子口袋关系提供了唯一的描述，而且还提供了口袋表面积、口袋体积和口袋深度的有效估计。可用性和实施源代码可在https://github.com/rdzhao/ProteinPocketDetection.上获得网络服务器可从http://weilab.math.msu.edu/PPD/.获得
Motivation Protein pocket information is invaluable for drug target identification, agonist design, virtual screening and receptor‐ligand binding analysis. A recent study indicates that about half holoproteins can simultaneously bind multiple interacting ligands in a large pocket containing structured sub‐pockets. Although this hierarchical pocket and sub‐pocket structure has a significant impact to multi‐ligand synergistic interactions in the protein binding site, there is no method available for this analysis. This work introduces a computational tool based on differential geometry, algebraic topology and physics‐based simulation to address this pressing issue. Results We propose to detect protein pockets by evolving the convex hull surface inwards until it touches the protein surface everywhere. The governing partial differential equations (PDEs) include the mean curvature flow combined with the eikonal equation commonly used in the fast marching algorithm in the Eulerian representation. The surface evolution induced Morse function and Reeb graph are utilized to characterize the hierarchical pocket and sub‐pocket structure in controllable detail. The proposed method is validated on PDBbind refined sets of 4414 protein‐ligand complexes. Extensive numerical tests indicate that the proposed method not only provides a unique description of pocket‐sub‐pocket relations, but also offers efficient estimations of pocket surface area, pocket volume and pocket depth. Availability and implementation Source code available at https://github.com/rdzhao/ProteinPocketDetection. Webserver available at http://weilab.math.msu.edu/PPD/.