Molecular Dynamics Simulations of Forced Unbending of Integrin αVβ3

Integrins may undergo large conformational changes during activation, but the dynamic processes and pathways remain poorly understood. We used molecular dynamics to simulate forced unbending of a complete integrin αVβ3 ectodomain in both unliganded and liganded forms. Pulling the head of the integrin readily induced changes in the integrin from a bent to an extended conformation. Pulling at a cyclic RGD ligand bound to the integrin head also extended the integrin, suggesting that force can activate integrins. Interactions at the interfaces between the hybrid and β tail domains and between the hybrid and epidermal growth factor 4 domains formed the major energy barrier along the unbending pathway, which could be overcome spontaneously in ∼1 µs to yield a partially-extended conformation that tended to rebend. By comparison, a fully-extended conformation was stable. A newly-formed coordination between the αV Asp457 and the α-genu metal ion might contribute to the stability of the fully-extended conformation. These results reveal the dynamic processes and pathways of integrin conformational changes with atomic details and provide new insights into the structural mechanisms of integrin activation.Author Summary: Proteins can regulate their functions via conformational changes. One example is integrins, which are transmembrane receptors mediating cell-cell and cell-matrix adhesions. Inactive integrins may assume a bent conformation with low affinities for ligands unable to support adhesions. Intracellular or extracellular stimuli induce large scale changes from the bent to an extended conformation, resulting in active integrins with high affinities for ligands to mediate strong adhesions. We used molecular dynamics simulations to reveal the dynamics and pathways of integrin unbending in atomic details. Critical interactions in this process were identified. This study not only sheds light on the structural mechanisms of integrin activation, but also exemplifies allosteric regulations of protein functions.