Prediction of α _IIb β ₃ integrin structures along its minimum free energy activation pathway

The adhesion protein integrin is a transmembrane heterodimer that plays a pivotal role in cellular processes such as cell signaling and cell migration. To execute its function, integrin undergoes extensive conformational changes from a bent-closed to an extended-open state. Resolving the structures across these changes remains a challenge with both experimental and computational methods, but is crucial for understanding the activation mechanism of integrin. We address this challenge for the platelet integrin α _IIb β ₃ by employing finite temperature string method with structures of the images along the initial guess path generated by a multiscale data-driven framework. The full-length all-atom structures along the resulting minimum free energy path between the inactive bent-closed and active extended-open states of α _IIb β ₃ integrin are consistent with a variety of experimentally resolved structures. Changes in these predicted structures along the path show that the extension and separation of the α and β subunits from the bent-closed to the extended-open state require correlated movements between the subdomain pairs in α _IIb β ₃ . These results provide new insights into integrin activation mechanism and the predicted structures have potential applications in guiding the design of integrin targeting therapeutics.