Nonequilibrium Modeling of the Elementary Step in PDZ3 Allosteric Communication.

While allostery is of paramount importance for protein signaling and regulation, the underlying dynamical process of allosteric communication is not well understood. The PDZ3 domain represents a prime example of an allosteric single-domain protein, as it features a well-established long-range coupling between the C-terminal α-helix and ligand binding. In an intriguing experiment, Hamm and co-workers employed photoswitching of the α-helix to initiate a conformational change of PDZ3 that propagates from the C-terminus to the bound ligand within 200 ns. Performing extensive nonequilibrium molecular dynamics simulations, the modeling of the experiment reproduces the measured time scales and reveals a detailed picture of the allosteric communication in PDZ3. In particular, a correlation analysis identifies a network of contacts connecting the α-helix and the core of the protein, which move in a concerted manner. Representing a one-step process and involving direct α-ligand contacts, this cooperative transition is considered as the elementary step in the propagation of conformational change.