Conformational Transition of Glycoprotein Ibα Mutants in Flow Molecular Dynamics Simulation
Conformational Transition of Glycoprotein Ibα Mutants in Flow Molecular Dynamics Simulation
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DOI：
10.1007/s12195-011-0171-1
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发表时间：
2011-09-01
影响因子：
2.8
通讯作者：
Zhu, Cheng
中科院分区：
文献类型：
--
作者：
Huang, Qingsheng;Lou, Jizhong;Zhu, Cheng
糖蛋白Ib α（GPIb α）与血管性血友病因子（VWF）相互作用，诱导血小板与受损血管壁的束缚和随后的止血过程。我们以前已经表明，GPIb α N的β-开关区域的构象可以通过流动来调节。流动诱导该区域中的环到β-发夹构象变化，这是流动增强GPIb α与VWF-A1结合的建议机制。为了进一步评价该机制并获得更完整的证据，我们对该β开关的野生型和一些突变体进行了流动分子动力学模拟。结果表明，功能获得突变G233 V、D235 V和K237 V促进了向β-发夹的构象转变，而功能丧失突变Q232 V阻碍了该转变。这种促进作用主要是由于β-发夹上配对残基的极性相似性提高，以及β-开关的一条链的柔性降低。功能获得突变局部地施加影响，仅影响突变残基附近的氢键。功能丧失突变体的障碍可能是非必需的疏水相互作用阻断构象变化。
Glycoprotein Ib alpha (GPIb alpha) interacts with von Willebrand factor (VWF) inducing the tethering of platelets to injured vessel walls and subsequent hemostasis process. We have previously shown that the conformation of the beta-switch region of GPIb alpha N can be regulated by flow. Flow induces a loop-to-beta-hairpin conformational change in this region, which is a suggested mechanism for the flow-enhanced binding of GPIb alpha to VWF-A1. To further evaluate the mechanism and obtain more complete evidences, here we performed flow molecular dynamics simulations of wild type and a number of mutants of the beta-switch. The results demonstrate that the gain-of-function mutations G233V, D235V, and K237V promote the conformational transition toward beta-hairpin, while the loss-of-function mutation Q232V impedes the transition. The promotion is caused mainly by the improved polarity similarity of the paired residues on the beta-hairpin, and also by the decreased flexibility of one strand of the beta-switch. The gain-of-function mutations exert the influence locally, affecting only hydrogen bonds near the mutated residues. The impediment of the loss-of-function mutant may be non-essential hydrophobic interactions blocking the conformational change.