A3/A1复合物对接及结构域之间相互作用的分子动力学研究  

Molecular Dynamics Study on Docking of A3/A1 and Interdomain Interactions

作　　者：李圆圆 宁志龙 吴建华[1] 方颖[1] LI Yuanyuan;NING Zhilong;WU Jianhua;FANG Ying(School of Bioscience and Bioengineering,South China University of Technology,Guangzhou 510006,China)

机构地区：[1]华南理工大学生物科学与工程学院,广州510006

出　　处：《医用生物力学》2020年第2期195-201,215,共8页Journal of Medical Biomechanics

基　　金：国家自然科学基金项目(11672109,11432006,11272125,31170887)。

摘　　要：目的探究血管性血友病因子(von Willbrand factor,v WF)A1、A3结构域间的相互作用及A3的2 M型突变W1745C对A3/A1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;再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-A3/A1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v WF分子内部A1与A3的相互作用阻碍A1与血小板的结合,而W1745C-A3突变则强化这种分子内部的相互作用,降低A1对血小板的亲和力。研究结果为深入揭示临床中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参考。Objective To investigate the interaction between von Wil ebrand factor(v WF)A1 and A3 domain,and type2 M mutant W1745 C-A3 effect on thermal stability and mechanical stability of A3/A1.Methods The crystal structures of A1 and A3 were downloaded from Protein Data Base(PDB).The wild-type(WT)A3/A1 structure was obtained by using Swarm Dock Server,then W1745 C-A3/A1 mutant was constructed by replacing the Trp1745 with Cys1745 in A3/A1.Through steered molecular dynamics simulation,formation and evolution of hydrogen bond and salt bridge between A1 and A3 interfaces were observed,and the differences in conformation,disrupted force and dissociation time between WT-A3/A1 and W1745 C-A3/A1 were compared.Results There were 5 pairs of hydrogen bonds with survival rate>0.2 and 1 pair of salt bridge with survival rate>0.5 between A1 and A2.The W1745 C-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 of stable salt bridge.Conclusions The interaction between A1 and A3 would hinder the binding sites of A1 to GPIbα,and the W1745 C-A3 mutation would further reduce the affinity of A1 to platelets.These results provide references for revealing the molecular mechanism of von Willebrand diseases in the clinic and developing the corresponding drugs targeted to hemostasis disorders.

关 键 词：血管性血友病因子 分子动力学模拟 柔性对接 机械稳定性 

分 类 号：R318.01[医药卫生—生物医学工程]