Molecular basis of the initial platelet adhesion in arterial thrombosis: Molecular dynamics simulations
Molecular basis of the initial platelet adhesion in arterial thrombosis: Molecular dynamics simulations
复制标题
动脉血栓形成中初始血小板粘附的分子基础：分子动力学模拟
DOI：
10.1016/j.jmgm.2012.04.002
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发表时间：
2012-07-01
影响因子：
2.9
通讯作者：
Sun, Yan
中科院分区：
文献类型：
--
作者：
Li, Jian;Zhang, Lin;Sun, Yan
血管性血液病因子（VWF） A1结构域和糖蛋白Ib α (GPIb α)之间的分子相互作用促进血小板的初始粘附和随后的动脉血栓形成。然而，人们对分子水平上的相互作用知之甚少。因此，利用分子动力学模拟和全原子模型研究了水和生理盐水中VWF A1结构域与GPIb α的结合动力学和相关分子相互作用。在水中观察到比生理盐水中更快的结合，并且在结合界面上观察到相反电荷的斑块。此外，分子力学-泊松-玻尔兹曼表面积分析表明，这种结合是由远距离静电相互作用促进的，然后由疏水相互作用维持。对于初始结合，热点包括GPIb α中的E14、E128、0175、D83、E151、D106、D63、E5、D18、E225、D235残基和VWF A1结构域的K608、K569、K644、R571、K572、R636、K599残基。然而，对于最终的络合物形成，72%的有利贡献来自疏水相互作用。结果提供了初步血小板粘附的分子洞察力。发现的热点将有利于开发新的血栓性疾病药物。(C) 2012爱思唯尔公司版权所有。
Molecular interactions between the von Willebrand factor (VWF) A1 domain and glycoprotein Ib alpha (GPIb alpha) promote the initial adhesion of platelets and subsequent arterial thrombus formation. However, little is understood about the interactions at a molecular level. Therefore, the binding dynamics and involved molecular interactions between VWF A1 domain and GPIb alpha in both water and physiological saline are investigated using molecular dynamics simulations and all-atom models. Faster binding is observed in water than that in physiological saline, and patches of opposite charges are observed at the binding interface. Moreover, molecular mechanics-Poisson-Boltzmann surface area analysis indicates that the binding is promoted by the long-range electrostatic interactions and then maintained by hydrophobic interactions. For the initial binding, the hot spots include the residues E14, E128, 0175, D83, E151, D106, D63, E5, D18, E225, D235 in GPIb alpha, and K608, K569, K644, R571, K572, R636, K599 in VWF A1 domain. For the final complex formation, however, 72% of the favorable contributions are from hydrophobic interactions. The results provided molecular insight into the initial platelet adhesion. The hot spots identified would be beneficial for developing novel drugs for thrombotic diseases. (C) 2012 Elsevier Inc. All rights reserved.