{Reference Type}: English Abstract
{Title}: [Molecular dynamics simulation of force-regulated interaction between talin and Rap1b].
{Author}: Yu Z;Ji Y;Huang W;Fang Y;Wu J;
{Journal}: Sheng Wu Yi Xue Gong Cheng Xue Za Zhi
{Volume}: 40
{Issue}: 4
{Year}: 2023 Aug 25
暂无{DOI}: 10.7507/1001-5515.202208022
{Abstract}: The binding of talin-F0 domain to ras-related protein 1b (Rap1b) plays an important role in the formation of thrombosis. However, since talin is a force-sensitive protein, it remains unclear whether and how force regulates the talin-F0/Rap1b interaction. To explore the effect of force on the binding affinity and the dynamics mechanisms of talin-F0/Rap1b, molecular dynamics simulation was used to observe and compare the changes in functional and conformational information of the complex under different forces. Our results showed that when the complex was subjected to tensile forces, there were at least two dissociation pathways with significantly different mechanical strengths. The key event determining the mechanical strength difference between the two pathways was whether the β4 sheet of the F0 domain was pulled away from the original β1-β4 parallel structure. As the force increased, the talin-F0/Rap1b interaction first strengthened and then weakened, exhibiting the signature of a transition from catch bonds to slip bonds. The mechanical load of 20 pN increased the interaction index of two residue pairs, ASP 54-ARG 41 and GLN 18-THR 65, which resulted in a significant increase in the affinity of the complex. This study predicts the regulatory mechanism of the talin-F0/Rap1b interaction by forces in the intracellular environment and provides novel ideas for the treatment of related diseases and drug development.<BR>踝蛋白（Talin）的F0结构域与Ras相关蛋白1b（Rap1b）的结合对血栓形成至关重要。然而Talin作为一种力敏感蛋白，力能否调控Talin-F0/Rap1b的相互作用以及如何调控，尚不明晰。为探究力对Talin-F0/Rap1b结合亲和力的影响以及相应动力学机制，采用拉伸分子模拟的手段，以Talin-F0/Rap1b复合物结构为对象，观察并比较分析不同作用力下复合物功能-构象信息的变化情况。结果表明，复合物受力解离过程至少存在两种路径且两者机械强度有显著差异，决定机械强度差异的关键事件是F0结构域的β4片层是否从原先的β1-β4片层平行结构被拉出。随着力的增大，复合物的相互作用将先增强后减弱，表现出“逆锁-滑移键”的特性。ASP 54-ARG 41、GLN 18-THR 65这两对残基的相互作用受到力学信号的调控，20 pN的机械力能显著增强这些残基的作用指数，从而导致复合物结合亲和力大幅提升。本研究预报了胞内环境中力对Talin-F0/Rap1b相互作用的调控机制，为相关疾病的治疗和药物的开发提供了新的思路。.