Allosteric Communication Mediated by Protein Contact Clusters: A Dynamical Model

Describing the puzzling phenomenon of long-range communication between distant protein sites, allostery is of paramount importance in biomolecular regulation and signal transduction. It is commonly assumed to arise from a conformational rearrangement of the protein, although the underlying dynamical process has remained largely elusive. 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 multistep 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 ∼500 μs) 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 effects the nonlocal coupling between distant clusters. A time scale analysis reveals dynamics from nano- to microseconds, which are in excellent agreement with the experimentally measured time scales. While the simulation of larger systems may require enhanced sampling techniques, it is expected that the general picture of allostery mediated by communicating contact clusters will still be applicable.