Allosteric communication mediated by protein contact clusters: A dynamical model

Abstract: Allostery refers to the puzzling phenomenon of long-range communication between distant sites in proteins. Despite its importance in biomolecular regulation and signal transduction, the underlying dynamical process is not well understood. This study introduces a dynamical model of allosteric communication based on "contact clusters"-localized groups of highly correlated contacts that facilitate interactions between secondary structures. The model shows that allostery involves a multi-step process with cooperative contact changes within clusters and communication between distant clusters mediated by rigid secondary structures. Considering time-dependent experiments on a photoswitchable PDZ3 domain, extensive (in total $\sim 500\,\mu$s) molecular dynamics simulations are conducted that directly monitor the photoinduced allosteric transition. The structural reorganization is illustrated by the time evolution of the contact clusters and the ligand, which affects the nonlocal coupling between distant clusters. A timescale analysis reveals dynamics from nano- to microseconds, which are in excellent agreement with the experimentally measured timescales.