Contributions of the individual domains of αβ integrin to its extension: Insights from multiscale modeling.

The platelet integrin αβ undergoes long-range conformational transitions between bent and extended conformations to regulate platelet aggregation during hemostasis and thrombosis. However, how exactly αβ transitions between conformations remains largely elusive. Here, we studied how transitions across bent and extended-closed conformations of αβ integrin are regulated by effective interactions between its functional domains. We first carried out μs-long equilibrium molecular dynamics (MD) simulations of full-length αβ integrins in bent and intermediate conformations, the latter characterized by an extended headpiece and closed legs. Then, we built heterogeneous elastic network models, perturbed inter-domain interactions, and evaluated their relative contributions to the energy barriers between conformations. Results showed that integrin extension emerges from: (i) changes in interfaces between functional domains; (ii) allosteric coupling of the head and upper leg domains with flexible lower leg domains. Collectively, these results provide new insights into integrin conformational activation based on short- and long-range interactions between its functional domains and highlight the importance of the lower legs in the regulation of integrin allostery.