Computational studies of protein regulation by post-translational phosphorylation

Post-translational modifications of amino acids in proteins are important in regulating many cellular functions. Phosphorylation is the most well-studied post-translational modification, both experimentally and computationally. The introduction of a phosphate group, generally carrying a −2 charge at neutral pH, is a large electrostatic perturbation that alters the free energy landscape underlying protein structure and interactions. Much progress has been made in studying the structural basis of protein regulation by phosphorylation, and atomistic computational simulations are increasingly being used to complement and drive experiment. We focus on three areas: (1) protein kinases, where computational simulations have helped to provide a better understanding of the structural consequences of activation loop and glycine-rich loop phosphorylation; (2) peptide systems, for which molecular dynamics has enabled understanding of structural ordering induced by phosphorylation, and (3) phosphoregulation of membrane proteins. As the use of computation to elucidate principles of phosphoregulation is in its infancy, we also discuss areas for future progress.