A3/A1复合物的对接及结构域之间相互作用的分子动力学研究
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华南理工大学 生物科学与工程学院

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国家自然科学基金(11672109,11432006,11272125,31170887)。


Docking of A3/A1 and interdomain interactions study by Molecular dynamics
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South China University of Technology

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    摘要:

    目的 探究VWFA1、A3结构域间的相互作用及A3的2M型突变W1745C对A1/A3热稳定性和机械稳定性的影响。 方法 A1、A3的晶体结构取自PDB数据库,首先通过柔性对接获得WT-A3/A1(野生型)复合物结构;进而利用计算机突变技术构建W1745C-A3/A1复合物体系;最后采用拉伸分子动力学模拟,观察接触面氢键和盐桥的形成与演化,对比分析WT-A3/A1与W1745C-A1/A3在复合物构象、解离力和解离时间的差异。 结果 WT-A3/A1接触面之间存在5对生存率大于0.2的氢键和1对生存率大于0.5的盐桥;W1745C-A3突变提高了结合面氢键的生存率并增加1对稳定盐桥,从而能够抵抗更大的拉伸力,延缓A1/A3的解离。 结论 VWF分子内部A1与A3的相互作用阻碍了A1与血小板的结合,而W1745C-A3突变则强化了这种分子内部的相互作用,降低了A1对血小板的亲和力。研究结果可为深入揭示突变导致的血管性血友病的分子机制及相应药物研制提供帮助。

    Abstract:

    Objective To investigate the interaction between von Willebrand factor (VWF) A1 and A3 domain, and type 2M mutant W1745C-A3 effect on the thermal stability and mechanical stability of A1/A3. Methods The crystal structures of A1 and A3 were downloaded from Protein Data Base (PDB). Using SwarmDock Server to obtain wild-type (WT) A3/A1 structure, then W1745C-A3/A1 mutant was constructed by replacing the Trp1745 with Cys1745 in WT-A3/A1. Through Steered molecular dynamics simulation, the formation and evolution of hydrogen bond and salt bridge between A1 and A2 interfaces were observed, and the differences on conformation, disrupted force and dissociation time between WT-A1/A3 and W1745C-A3/A1 were be analyzed and compared. Results There were 5 pairs of hydrogen bonds with survival rate > 0.2 and 1 pair salt bridge with survival rate > 0.5 between A1 and A2. The W1745C-A3/A1 complex could withstand greater disrupted force and longer dissociation time compared with WT-A3/A1, by improving the stability of hydrogen bonds and increasing 1 pair stable salt bridge. Conclusions The interaction between A1 and A3 would hinder the binding sites of A1 to GPIbα, and the W1745C-A3 mutation would further reduce the affinity of A1 to platelets. These results would be helpful for revealing the molecular mechanism of von Willbrand disease and developing the corresponding drugs targeted to hemostasis disorders.

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  • 收稿日期:2019-03-26
  • 最后修改日期:2019-04-24
  • 录用日期:2019-04-30
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