Activation of Integrin: A Multiscale Computational Study

Abstract

Despite the importance of integrin proteins in cell signal transduction and force generation, the mechanism of action is not understood at the atomic level. To date, no experimental method has been able to probe the structure of integrin proteins in their open, force-activated state. To gain a better understanding of the transformation of the inactive, closed, state to an active state of the integrin, we are employing advanced computational techniques that will allow us to more quickly sample the conformational change and probe the pathway of the transformation. To make connection with the experimental studies, we have first studied the effect of single and double amino acid substitutions to the wild type integrin. Our simulations reveal certain mutants which destabilize the closed state by increasing the kink angle of the extracellular region and distance between the transmembrane region of the alpha and beta subunits of the integrin. We have also developed a coarse-grained model based on our atomistic simulation data, and are using that model to probe the transition of integrin to the open state.