Mapping paratope on antithrombotic antibody 6B4 to epitope on platelet glycoprotein Ibalpha via molecular dynamic simulations.
Mapping paratope on antithrombotic antibody 6B4 to epitope on platelet glycoprotein Ibalpha via molecular dynamic simulations.
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通过分子动力学模拟将抗血栓抗体 6B4 上的互补位映射到血小板糖蛋白 Ibalpha 上的表位
DOI：
10.1371/journal.pone.0042263
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Wu J
中科院分区：
文献类型：
--
作者：
Fang X;Fang Y;Liu L;Liu G;Wu J
血小板受体糖蛋白Ibα（GPIbα）与血管性血友病因子（vWF）A1结构域的结合是生理性止血和病理性血栓形成的关键步骤，可启动血小板粘附于血管损伤部位的血管内皮下。GPIbα的功能获得性突变导致血小板与vWF异常高亲和力结合，并可导致血栓形成，这是一种引起心脏病发作和卒中的确切并发症。在众多抗血栓单克隆抗体中，6 B4是一种在静态和流动条件下均能有效抑制GPIbα与vWF-A1相互作用的单克隆抗体。利用突变实验定位互补位表位是抗血栓单抗研究的传统方法，但该方法成本高、耗时长。本文提出了一种新的计算方法，结合同源模建、刚体对接、自由和转向分子动力学（MD）模拟来识别6 B4上的关键互补位残基及其GPIbα上的配对残基，并假设稳定的氢键和盐桥是连接互补位和表位残基的重要纽带。基于6 B4与GPIbα结合的最佳模型，通过自由和转向分子动力学模拟，研究了结合位点上所有氢键和盐桥的存活率和断裂时间，并分别作为键的热稳定性和机械稳定性的指标.五个主要的互补位残基与他们的合作伙伴预测与他们的高存活率和/或涉及的氢键的长断裂时间，或与他们的氢键稳定指数排名前5位。结果表明，该方法在配体-受体相互作用的分子基础、抗血栓单克隆抗体和其他抗体的研究以及生物分子药物的理论设计等方面具有广阔的应用前景。
Binding of platelet receptor glycoprotein Ibα (GPIbα) to the A1 domain of von Willebrand factor (vWF) is a critical step in both physiologic hemostasis and pathologic thrombosis, for initiating platelet adhesion to subendothelium of blood vessels at sites of vascular injury. Gain-of-function mutations in GPIbα contribute to an abnormally high-affinity binding of platelets to vWF and can lead to thrombosis, an accurate complication causing heart attack and stroke. Of various antithrombotic monoclonal antibodies (mAbs) targeting human GPIbα, 6B4 is a potent one to inhibit the interaction between GPIbα and vWF-A1 under static and flow conditions. Mapping paratope to epitope with mutagenesis experiments, a traditional route in researches of these antithrombotic mAbs, is usually expensive and time-consuming. Here, we suggested a novel computational procedure, which combines with homology modeling, rigid body docking, free and steered molecular dynamics (MD) simulations, to identify key paratope residues on 6B4 and their partners on GPIbα, with hypothesis that the stable hydrogen bonds and salt bridges are the important linkers between paratope and epitope residues. Based on a best constructed model of 6B4 bound with GPIbα, the survival ratios and rupture times of all detected hydrogen bonds and salt bridges in binding site were examined via free and steered MD simulations and regarded as indices of thermal and mechanical stabilizations of the bonds, respectively. Five principal paratope residues with their partners were predicted with their high survival ratios and/or long rupture times of involved hydrogen bonds, or with their hydrogen bond stabilization indices ranked in top 5. Exciting, the present results were in good agreement with previous mutagenesis experiment data, meaning a wide application prospect of our novel computational procedure on researches of molecular of basis of ligand-receptor interactions, various antithrombotic mAbs and other antibodies as well as theoretically design of biomolecular drugs.
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影响因子：
3
作者：
Arcangeli, Caterina;Cantale, Cristina;Rosato, Vittorio
通讯作者：
Rosato, Vittorio
影响因子：
4.8
作者：
Fontayne, Alexandre;De Maeyer, Bauke;Deckmyn, Hans
通讯作者：
Deckmyn, Hans
影响因子：
7.5
作者：
Dai, KS;Zhu, HP;Ruan, CG
通讯作者：
Ruan, CG
影响因子：
2.8
作者：
Huang, Qingsheng;Lou, Jizhong;Zhu, Cheng
通讯作者：
Zhu, Cheng
DOI：
10.1073/pnas.0801965105
发表时间：
2008-09-16
影响因子：
11.1
作者：
Lou, Jizhong;Zhu, Cheng
通讯作者：
Zhu, Cheng