Contributions of the individual domains of α IIb β 3 integrin to its extension: Insights from multiscale modeling.

The platelet integrin α IIb β 3 undergoes long-range conformational transitions between bent and extended conformations to regulate platelet aggregation during hemostasis and thrombosis. However, how exactly α IIb β 3 transitions between conformations remains largely elusive. Here, we studied how transitions across bent and extended-closed conformations of α IIb β 3 integrin are regulated by effective interactions between its functional domains. We first carried out μs-long equilibrium molecular dynamics (MD) simulations of full-length α IIb β 3 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.