Modeling the effect of pathogenic mutations on the conformational landscape of protein kinases

Abstract

Most proteins assume different conformations to perform their cellular functions. This conformational dynamics is physiologically regulated by binding events and post-translational modifications, but can also be affected by pathogenic mutations. Atomistic molecular dynamics simulations complemented by enhanced sampling approaches are increasingly used to probe the effect of mutations on the conformational dynamics and on the underlying conformational free energy landscape of proteins. In this short review we discuss recent successful examples of simulations used to understand the molecular mechanism underlying the deregulation of physiological conformational dynamics due to non-synonymous single point mutations. Our examples are mostly drawn from the protein kinase family.