Allosteric Communication Mediated by Protein Contact\nClusters: A Dynamical Model

Describing the puzzling\nphenomenon of long-range communication\nbetween distant protein sites, allostery is of paramount importance\nin biomolecular regulation and signal transduction. It is commonly\nassumed to arise from a conformational rearrangement of the protein,\nalthough the underlying dynamical process has remained largely elusive.\nThis study introduces a dynamical model of allosteric communication\nbased on “contact clusters”localized groups\nof highly correlated contacts that facilitate interactions between\nsecondary structures. The model shows that allostery involves a multistep\nprocess with cooperative contact changes within clusters and communication\nbetween distant clusters mediated by rigid secondary structures. Considering\ntime-dependent experiments on a photoswitchable PDZ3 domain, extensive\n(in total ∼500 μs) molecular dynamics simulations are\nconducted that directly monitor the photoinduced allosteric transition.\nThe structural reorganization is illustrated by the time evolution\nof the contact clusters and the ligand, which effects the nonlocal\ncoupling between distant clusters. A time scale analysis reveals dynamics\nfrom nano- to microseconds, which are in excellent agreement with\nthe experimentally measured time scales. While the simulation of larger\nsystems may require enhanced sampling techniques, it is expected that\nthe general picture of allostery mediated by communicating contact\nclusters will still be applicable.