Contact cluster modeling of allosteric communication in PDZ domains

TL;DR

This study introduces a contact cluster model to understand allosteric communication in PDZ domains, revealing modular contact groups that facilitate long-range signaling through dynamic, cooperative interactions.

Contribution

The paper presents a novel contact cluster framework validated by extensive molecular dynamics simulations to elucidate allosteric mechanisms in PDZ domains.

Findings

Identified recurring contact clusters as structural modules in PDZ domains.

Linked contact cluster motions to the characteristic time scales of protein responses.

Demonstrated the generality of the contact cluster model across different domains and perturbations.

Abstract

Allostery, the intriguing phenomenon of long-range communication between distant sites in proteins, plays a central role in biomolecular regulation and signal transduction. While it is commonly attributed to conformational rearrangements, the underlying dynamical mechanisms remain poorly understood. The contact cluster model of allostery [J. Chem. Theory Comput. 2024, 20, 10731-10739] identifies localized groups of highly correlated contacts that mediate interactions between secondary structure elements. This framework proposes that allostery proceeds through a multistep process involving cooperative contact changes within clusters and communication between distant clusters, transmitted through rigid secondary structures. To demonstrate the validity and generality of the model, this Perspective employs extensive molecular dynamics simulations ($\sim1\,$ms total simulation time) of four different photoswitchable PDZ domains and studies how different domains, ligands, and perturbations influence both the contact clusters and their dynamical evolution. These analyses reveal several recurring clusters that represent shared flexible structural modules, such as loops connecting $\beta$-sheets, and show that the characteristic time scales of the nonequilibrium protein response can be directly associated with the motions of individual contact clusters. Thus, the dynamic decomposition of PDZ domains into contact clusters uncovers a modular, dynamics-based architecture that underlies and facilitates long-range allosteric communication.