Computer prediction of paratope on antithrombotic antibody 10B12 and epitope on platelet glycoprotein VI via molecular dynamics simulation.
Computer prediction of paratope on antithrombotic antibody 10B12 and epitope on platelet glycoprotein VI via molecular dynamics simulation.
复制标题
通过分子动力学模拟计算机预测抗血栓抗体10B12上的互补位和血小板糖蛋白VI上的表位
DOI：
10.1186/s12938-016-0272-0
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发表时间：
2016-12-28
影响因子：
3.9
通讯作者：
Wu J
中科院分区：
文献类型：
--
作者：
Liu W;Liu G;Zhou H;Fang X;Fang Y;Wu J
免疫球蛋白样受体糖蛋白VI（GPVI）和胶原之间的相互作用在血小板活化和粘附中起着重要作用。针对GPVI的抗血栓药物中，抗体10 B12具有阻断GPVI-胶原相互作用的潜力，但关于10 B12互补位和GPVI表位的研究较少。沿着我们前期工作中提出的计算机策略中的途径，通过同源模建和刚体对接构建了10 B12/GPVI复合物模型，并利用分子动力学（MD）模拟方法对10 B12上的互补位残基及其在GPVI上的配对残基进行了检测。通过自由和转向MD模拟量化，氢键和盐桥的稳定性被用来排列界面残基对10 B12和GPVI结合的贡献。用本方法预测了10 B12与GPVI相互作用中的12个关键残基和7个非关键残基。除了12个关键残基外，两个是表位残基（LYS 41和LYS 59），其已经通过先前的突变实验鉴定，以及其他，包括四个表位残基（GPVI上的ARG 38、SER 44、ARG 46和TYR 47）和六个互补位残基（10 B12上的GLU 1、ASP 98、GLU 102、ASP 107、ASP 108和ASP 111）是新发现的，可能对10 B12-GPVI结合也很重要。在先前的突变实验中已经说明了GPVI上的七个预测的C37 BL残基。结合同源模建、刚体对接和分子动力学模拟的计算机策略可以有效地将抗血栓抗体10 B12的互补位映射到GPVI的表位上，在药物发现和抗体研究中具有巨大的潜力。
Interaction between immunoglobulin-like receptor glycoprotein VI (GPVI) and collagen plays a central role in platelet activation and sequent firm adhesion. Of various antithrombotic agents targeting GPVI, antibody 10B12 is of great potential to block the GPVI-collagen interaction, but less is known about 10B12 paratope and GPVI epitope. Along the pathway in the computer strategy presented in our previous work, the 10B12/GPVI complex model was constructed through homology modeling and rigid-body docking, and the molecular dynamics (MD) simulation was used to detect the paratope residues on 10B12 and their partners on GPVI. Quantified by free and steered MD simulations, the stabilities of hydrogen bonds and salt bridges were used to rank the contributions of interface residues to binding of 10B12 and GPVI. We predicted 12 key and seven dispensable residues in interaction of 10B12 to GPVI with present computational procedure. Besides of the 12 key residues, two are epitope residues (LYS41 and LYS59) which had been identified by previous mutation experiments, and others, including four epitope residues (ARG38, SER44, ARG46 and TYR47 on GPVI) and six paratope residues (GLU1, ASP98, GLU102, ASP107, ASP108 and ASP111 on 10B12), were newly found and also might be important for the 10B12–GPVI binding. The seven predicted dispensable residues on GPVI were had been illustrated in previous mutation experiments. The present computer strategy combining homology modeling, rigid body docking and MD simulation was illustrated to be effective in mapping paratope on antithrombotic antibody 10B12 to epitope on GPVI, and have large potential in drug discovery and antibody research.