分子动力模拟法识别GPVI和10B12界面上的关键氨基酸残基  

Identifying the Critical Amino Acid Residues in the Interface between GPVI and 10B12 through Molecular Dynamics Simulation

作　　者：周慧云[1] 刘文平[1] 刘广建[1] 方颖[1] 吴建华[1] 

机构地区：[1]华南理工大学生物科学与工程学院,广州510006

出　　处：《生物物理学报》2013年第9期669-680,共12页Acta Biophysica Sinica

基　　金：国家自然科学基金项目(11072080;31170887;11272125);广东省自然科学基金项目(S2011010005451);教育部博士点基金项目(20110172110030)~~

摘　　要：血小板上免疫球蛋白样受体GPVI与血管内皮下胶原的结合是血小板激活和稳定粘附的中心环节,单克隆抗体10B12因能抑制GPVI与胶原的结合而受到关注。为识别GPVI/10B12上的关键残基,作者提出了一种结合同源模建、刚性对接和分子动力学模拟的计算方法,通过观察系统平衡和自由分子动力学模拟过程中GPVI/10B12复合物结合面上氢键和盐桥的形成和演化,分析计算它们的生存率,最后引入残基相互作用指数RII来度量参与相互作用残基的重要性。计算结果被突变实验证实有很高的准确度和特异性。说明RII的计算机策略能很好地检测和预报结合面的关键残基。Binding of immunoglobulin（Ig）-like receptor GPVI to collagen is essential for platelet activation and sequent stable adhesion. For various antithrombotic monoclonal antibodies targeting GPVI, 10B12 is a potent one to inhibit the interaction between GPVI and collage. Here, a novel computational procedure, which combines with homology modeling, rigid body docking and free molecular dynamics simulations, was proposed to identify key paratope residues on 10B12 and their partners on GPVI. Through the system equilibrium and free molecular dynamics simulations, the formation and evolution of hydrogen bonding and salt bridge on the binding sites of GPVI and 10B12 were observed and analyzed by VMD. Then a residue interaction index（RII）, which is scored with the survival ratios of salt bridges and/or hydrogen bonds involved in interaction of a residue to other（s）, was introduced to use as a criterion of the residue’s role in interaction between receptor and ligend. With hypothesis that an epitope residue is important for its RII value larger than 0.5, all key epitope residues confirmed via mutagenesis experiments were shown in the predicted results, and 6 of 7 noncritical residues confirmed by experiments were excluded. The results demonstrated that this novel approach is useful for computationally identifying the key residues of antibody such as 10B12bound with GPVI. The computer strategy presented here should find its application in the traditional mutagenesis experiments and the computer-aided antibody drugs design.

关 键 词：GPVI 10B12 同源模建 刚性对接 分子动力学模拟 关键残基 

分 类 号：Q615[生物学—生物物理学]