Prediction of αIIbβ3 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 IIb {beta}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 IIb {beta}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 and {beta} subunits from the bent-closed to the extended-open state require correlated movements between the subdomain pairs in IIb {beta}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. SIGNIFICANCEIntegrins are receptor proteins that mediate a number of critical cellular processes, but it remains challenging to resolve the molecular details of integrin activation by both experiments and simulations. We address this challenge by employing a computational method to study rare events and resolve the all-atom transient structures of a platelet integrin, IIb {beta}3. The resulting structures are in good agreement with experimentally resolved partial structures and additionally reveal correlated movements between the IIb {beta}3 integrin subdomain pairs during its transition from the inactive to the active conformational state. The structures predicted in this work have applications as therapeutic targets to address diseases linked to IIb {beta}3 integrin dysfunction, such as bleeding and thrombotic disorders.