PDF(Pubmed)
Abstract：
Integrin αIIbβ3 mediates platelet aggregation by binding the Arginyl-Glycyl-Aspartic acid (RGD) sequence of fibrinogen. RGD binding occurs at a site topographically proximal to the αIIb and β3 subunits, promoting the conformational activation of the receptor from bent to extended states. While several experimental approaches have characterized RGD binding to αIIbβ3 integrin, applying computational methods has been significantly more challenging due to limited sampling and the need for a priori information regarding the interactions between the RGD peptide and integrin. In this study, we employed all-atom simulations using funnel metadynamics (FM) to evaluate the interactions of an RGD peptide with the αIIb and β3 subunits of integrin. FM incorporates an external history-dependent potential on selected degrees of freedom while applying a funnel-shaped restraint potential to limit RGD exploration of the unbound state. Furthermore, it does not require a priori information about the interactions, enhancing the sampling at a low computational cost. Our FM simulations reveal significant molecular changes in the β3 subunit of integrin upon RGD binding and provide a free-energy landscape with a low-energy binding mode surrounded by higher-energy prebinding states. The strong agreement between previous experimental and computational data and our results highlights the reliability of FM as a method for studying dynamic interactions of complex systems such as integrin.
摘要：
整合素αIIbβ3通过结合纤维蛋白原的精氨酰-甘氨酰-天冬氨酸（RGD）序列介导血小板聚集。RGD结合发生在地形上靠近αIIb和β3亚基的位点，促进受体从弯曲状态到延伸状态的构象激活。虽然几种实验方法已经表征了RGD与αIIbβ3整合素的结合，由于有限的采样和需要有关RGD肽和整联蛋白之间相互作用的先验信息，应用计算方法变得更具挑战性。在这项研究中,我们使用漏斗元动力学（FM）进行全原子模拟，以评估RGD肽与整联蛋白的αIIb和β3亚基的相互作用。FM在选定的自由度上结合了依赖于外部历史的电势，同时应用漏斗形的约束电势来限制未束缚状态的RGD探索。此外，它不需要关于交互的先验信息，以较低的计算成本增强采样。我们的FM模拟揭示了RGD结合后整合素β3亚基的显着分子变化，并提供了具有低能结合模式的自由能景观，该模式被高能预结合状态包围。先前的实验和计算数据与我们的结果之间的强烈一致性凸显了FM作为研究诸如integrin之类的复杂系统的动态相互作用的方法的可靠性。
