力调控FLNa-Ig21/αⅡbβ3-CT复合物结构稳定性的分子动力学研究  

Structural Stability of Force-Regulated FLNa-Ig21/αⅡbβ3-CT Complexes by Molecular Dynamics Simulation

作　　者：任建芳 罗毅冲 吴建华[1] 方颖[1] REN Jianfang;LUO Yichong;WU Jianhua;FANG Ying(School of Biological Sciences and Engineering,Institute of Biomechanics,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、生物力学所,广州510006

出　　处：《医用生物力学》2024年第1期46-54,共9页Journal of Medical Biomechanics

基　　金：国家自然科学基金项目(12172137,12072117)。

摘　　要：目的探究力对FLNa-Ig21/αⅡbβ3-CT稳定性的影响及调控机制。方法FLNa-Ig21/αⅡbβ3-CT晶体结构取自PDB数据库。通过平衡和拉伸分子动力学模拟,分析复合物生理环境下稳定性以及力诱导的解折叠路径和力学稳定性。结果平衡过程中,FLNa-Ig21和αⅡbβ3-CT之间大部分盐桥和氢键的生存率小于0.5,其结合强度相对较弱;恒速度拉伸过程中,复合物可承受170~380 pN的拉力,其力学强度与力诱导的解离路径有关;在0~60 pN恒力条件下,复合物呈现“滑移键”趋势,且力的增加有利于αⅡbβ3近膜端R995-D723盐桥的解离和整合素的活化。结论力诱导的αⅡbβ3-CT近膜端异构可增强复合物的力学强度和解离时间的后移;突破20 pN阈值后,力正向调控整合素的活化。研究结果为深入揭示整合素αⅡbβ3活化的分子机制及相关靶向药物开发提供参考。Objective To investigate the effects of force on mechanical stability of FLNa-Ig21/αⅡbβ3-CT complex and the regulation mechanism.Methods The FLNa-Ig21/αⅡbβ3-CT crystal structures were taken from the PDB database.The stability of the complexes in a physiological environment as well as the unfolding path and mechanical stability induced by mechanical forces were analyzed using equilibrium and steered molecular dynamics simulations.Results During the equilibration,the survival rate of most salt bridge and hydrogen bonds was below 0.5,and the interactions between FLNa-Ig21 andαⅡbβ3-CT was relatively weak.During stretching at a constant velocity,the complex could withstand a tensile force of 70-380 pN,and its mechanical strength depended on the force-induced dissociation path.Under a constant force of 0-60 pN,the complexes exhibited a slipping-bond trend,and the force increase facilitated the breakage of the R995-D723 salt bridge and the activation ofαⅡbβ3 integrin.Conclusions The force-induced allostery ofαⅡbβ3-MP enhanced the complex mechanical strength and delayed FLNa-Ig21 dissociation fromαⅡbβ3-CT.After breaking through the 20 pN threshold,force positively regulated the activation ofαⅡbβ3 integrin.These results provide insights into the molecular mechanism ofαⅡbβ3 activation and the development of related targeted drugs.

关 键 词：血小板整合素 分子动力学模拟 解折叠路径 力学强度 力学调控机制 

分 类 号：R318.01[医药卫生—生物医学工程]