Q-SiteFinder: an energy-based method for the prediction of protein-ligand binding sites
Q-SiteFinder: an energy-based method for the prediction of protein-ligand binding sites
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DOI：
10.1093/bioinformatics/bti315
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发表时间：
2005-05-01
期刊：
影响因子：
5.8
通讯作者：
Jackson, RM
中科院分区：
文献类型：
--
作者：
Laurie, ATR;Jackson, RM
动机：识别蛋白质上配体结合位点的位置对于分子对接、从头药物设计以及功能位点的结构识别和比较等一系列应用至关重要。在这里，我们描述了一种称为 Q-SiteFinder 的配体结合位点预测新方法。它利用蛋白质和简单的范德华探针之间的相互作用能来定位能量上有利的结合位点。能量上有利的探针位点根据其空间接近度进行聚类，然后根据每个聚类内位点的相互作用能量总和对聚类进行排序。结果：使用 Q-SiteFinder 测试的 90% 的蛋白质中，前三个预测位点中至少有一个成功预测。该成功率高于常用的使用几何标准的口袋检测算法（Pocket-Finder）。此外，在生成准确映射到配体坐标的预测位点方面，Q-SiteFinder 的效率是 Pocket-Finder 的两倍。它还生成具有本研究中检查的方法的最低平均体积的预测位点。与口袋检测不同，预测位点的体积似乎显示出对蛋白质体积的相对较低的依赖性，并且在体积上与其包含的配体相似。限制口袋的大小对于减少对接和从头药物设计或位点比较所需的搜索空间很重要。该方法可应用于结构基因组学研究，其中蛋白质结合位点仍未表征，因为未结合蛋白质的 86% 成功率似乎仅略低于配体结合蛋白质。
Motivation: Identifying the location of ligand binding sites on a protein is of fundamental importance for a range of applications including molecular docking, de novo drug design and structural identification and comparison of functional sites. Here, we describe a new method of ligand binding site prediction called Q-SiteFinder. It uses the interaction energy between the protein and a simple van der Waals probe to locate energetically favourable binding sites. Energetically favourable probe sites are clustered according to their spatial proximity and clusters are then ranked according to the sum of interaction energies for sites within each cluster.Results: There is at least one successful prediction in the top three predicted sites in 90% of proteins tested when using Q-SiteFinder. This success rate is higher than that of a commonly used pocket detection algorithm (Pocket-Finder) which uses geometric criteria. Additionally, Q-SiteFinder is twice as effective as Pocket-Finder in generating predicted sites that map accurately onto ligand coordinates. It also generates predicted sites with the lowest average volumes of the methods examined in this study. Unlike pocket detection, the volumes of the predicted sites appear to show relatively low dependence on protein volume and are similar in volume to the ligands they contain. Restricting the size of the pocket is important for reducing the search space required for docking and de novo drug design or site comparison. The method can be applied in structural genomics studies where protein binding sites remain uncharacterized since the 86% success rate for unbound proteins appears to be only slightly lower than that of ligand-bound proteins.