1.华南理工大学 生物科学与工程学院;2.南方医科大学 基础医学院人体解剖学国家重点学科
目的 探究β2/FLNa相互作用的力学调控机制、磷酸化效应与分子结构基础。方法 β2/FLNa-WT和T758P晶体结构取自PDB，施行分子动力学（MD）模拟，采用MM/PBSA方法计算复合物结合自由能变化，并分析构象演化与残基相互作用等数据。结果 β2整合素THR758磷酸化修饰后，复合物的结合自由能下降，拉力累积降低。单纯的力学信号刺激下，β2/FLNa复合物的解离呈现出双相力依赖特性，而磷酸化后复合物的结合解离过程存在单纯的滑移键机制。结论 磷酸化将通过减弱M762-G2269残基相互作用，下调β2/FLNa复合物的结合亲和力，张力将双相调节复合物的解离。该研究结果有助于加深对炎症反应过程的认识，并为相关药物靶点的发现和抗体设计提供有益参考。
Objective To investigate the mechanistic regulatory mechanisms, phosphorylation effects and molecular structural basis of β2/FLNa interactions. Methods The crystal structures of β2/FLNa-WT and T758P complex were taken from PDB, and performed molecular dynamics simulations. The MM/PBSA method was used to calculate the binding free energy changes of the complex, and data on conformational evolution and residue interactions were analyzed. Results Following phosphorylation modification of β2 integrin THR758, the binding free energy of the complex and the pulling force accumulation were significantly decreased. The dissociation of β2/FLNa complex showed a biphasic force-dependent property under the stimulation of mechanical signals. A pure slip-bonding mechanism existed in the binding dissociation process of the complex after phosphorylation modification. Conclusions The phosphorylation would down-regulate the binding affinity of β2/FLNa complex by attenuating the M762-G2269 residue interaction, and tension would bidirectionally regulate the dissociation of the complex. The study contributes to a deeper understanding of the inflammatory response process, and provides useful references for the discovery of relevant drug targets and antibody design.