Nonequilibrium Modeling of the Elementary Step in PDZ3 Allosteric Communication

TL;DR

This study uses nonequilibrium molecular dynamics simulations to model and understand the elementary step of allosteric communication in the PDZ3 protein, revealing a contact network and cooperative transition mechanism.

Contribution

It provides a detailed nonequilibrium model of the allosteric signaling process in PDZ3, linking experimental timescales with molecular contact dynamics.

Findings

Reproduces experimental timescales of conformational change

Identifies a contact network mediating allosteric communication

Describes a cooperative, one-step transition involving direct ligand contacts

Abstract

While allostery is of paramount importance for protein signaling and regulation, the underlying dynamical process of allosteric communication is not well understood. 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 $\alpha_3$-helix and ligand binding. In an intriguing experiment, Hamm and coworkers employed photoswitching of the $\alpha_3$-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 timescales and reveals a detailed picture of the allosteric communication in PDZ3. In particular, a correlation analysis identifies a network of contacts connecting the $\alpha_3$-helix and the core of the protein, which move in a concerted manner. Representing a one-step process and involving direct $\alpha_3$-ligand contacts, this cooperative transition is considered as elementary step in the propagation of conformational change.