小分子配体模仿结合位点水分子:相同配体与不同蛋白靶点之间作用模式的计算研究  

Ligand Mimicking Binding-Site Waters: a Computational Investigation of Identical Ligands Bound with Unrelated Proteins

作　　者：户忠哲 徐顺[1,2] 张宝花[1,2] 房森彪 金钟[1,2] 

机构地区：[1]中国科学院计算机网络信息中心,北京100190 [2]中国科学院大学,北京100049 [3]北京生命科学研究所,北京102206

出　　处：《科研信息化技术与应用》2016年第5期36-42,共7页E-science Technology & Application

摘　　要：在计算化学和药物设计领域中,精确预测小分子配体的蛋白质靶标是一件极具挑战性工作,特别是那些与相同小分子配体相互作用,但蛋白间并不具有显著序列或结构相似性的靶标蛋白。为了研究相同小分子配体与不相关的蛋白质靶标之间的结合特性,我们使用蛋白水合效应分析(SPA)程序研究了33对药物靶蛋白结合位点水分子的结构特性。每个蛋白对中的两个蛋白质,均由可与相同配体小分子相结合的两个不相关的蛋白质组成。通过计算两蛋白质间的水化位点替代重叠率,我们发现共有高达73%的蛋白对中有着显著的水分子替代重叠率值。特别是我们发现相同小分子与不同蛋白相互作用时,或许存在一种特别的"识别代码",即小分子配体的功能基团与结合位点的水分子之间存在着较好的几何构型相似性。在无法确定小分子与蛋白相互作用模式时,可以依靠活性结合腔穴中水分子的结合构型特征,进行粗略估算与预测,对蛋白-配体相互作用模式研究有重要的实用价值。Accurate prediction of protein targets for a given ligand can be challenging in computational chemistry and drug design,especially since many target proteins do not share significant sequential or structural similarity with the original molecular target.To investigate the binding characteristics of identical ligands bound with unrelated protein targets,we analyzed the structural properties of binding-site waters for 33pairs of drug target proteins using a solvent property analysis（SPA）program.Each target pair consisted of two unrelated proteins bound with an identical ligand.The configuration of binding-site waters replaced by the ligand had a significant overlapping rate in 73%of target pairs.In particular,water molecules replaced by ligand functional groups that formed hydrogen bonds with catalytic-site residues shared a highly ordered geometric complementarity among the majority of protein pairs.Our results suggest that there is likely be a binding＂code＂that functions across different target sites for ligand recognition,identifiable by characteristic H-bonding with binding-site waters.Thus,computationally predicted binding-site waters may serve as a structural filter to enforce the binding mode prediction of a single ligand against different receptors.

关 键 词：蛋白水合效应分析 水化位点 结合模型 结合亲和力 分子模拟 

分 类 号：O561.3[理学—原子与分子物理]