一种基于分子动力学模拟来识别GPIbα与vWF-A1结合面上重要残基的新方法  

A novel approach for identifying the critical amino acid residues on binding site of GPIbα and vWF-A1 domain through molecular dynamics simulation

作　　者：窦甜甜[1] 吴建华[1] 刘广建[1] 方颖[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：《医用生物力学》2013年第6期606-614,共9页Journal of Medical Biomechanics

基　　金：国家自然科学基金资助项目(10972081;11072080)

摘　　要：目的发展一种识别受体与配体相互作用中关键氨基酸残基的计算机新方法。方法 GPIbα/vWF-A1的晶体结构取自PDB数据库;利用自由分子动力学模拟,观察GPIbα/vWF-A1复合物结合面上的盐桥和氢键的形成和演化;利用分析计算得到的这些盐桥和氢键的生存率的高低,作为度量相互作用残基对之重要性的判据。结果在GPIbα/vWF-A1的结合面上,GPIbα的21个残基和vWF-A1的21个残基显著参与了GPIbα和vWF-A1间的相互作用,这些残基中的20个已得到突变实验的证实。结论该方法能较好地预报和识别受体-配体相互作用中的关键残基,并可为传统的氨基酸残基突变实验和抗凝血栓药物设计提供指导。Objective To develop a novel computer method for identifying the critical amino acid residues in the receptor-ligand interactions. Methods GPIbα/vWF-A1 crystal structure was taken from Protein Data Bank （PDB code 1SQ0）. Free molecular dynamics simulations were performed to observe the formation and evolution of hydrogen bonding and salt bridge on the binding sites of GPIbα and vWF-A1 by VMD. A residue interaction index, which was scored with the survival ratios of salt bridges and/or hydrogen bonds involved in interaction of a residue to other（s）, was used as a criterion of the residue’s role in interaction between the receptor and ligand. Results In the interface, 21 residues in GPIbα and 21 residues in vWF-A1 were significantly identified to participate in the interaction between GPIbα and vWF-A1; 20 of these 42 key residues were verified by previous mutagenesis experiments. Conclusions This novel approach is useful for computationally identifying the key residues involved in GPIbα-vWF interaction, and has potential in developing new strategy for the traditional mutagenesis experiments and the antithrombotic mAbs drug design.

关 键 词：分子动力学模拟 关键残基 受体 配体 

分 类 号：R318.01[医药卫生—生物医学工程]