Allosteric Communication Mediated by Protein Contact Clusters: A Dynamical Model.

Area of Science:

• Biophysics
• Structural Biology
• Biochemistry

Background:

• Allostery enables long-range communication between distant protein sites, vital for biomolecular regulation and signal transduction.
• The precise dynamical mechanisms underlying allosteric regulation, particularly the transition process, remain largely elusive.
• Conformational rearrangements are typically assumed to drive allosteric effects, but the dynamic pathways are not well understood.

Purpose of the Study:

• To introduce and validate a novel dynamical model for allosteric communication.
• To elucidate the step-by-step process of allosteric signal transmission.
• To correlate computational findings with experimental observations of allosteric transitions.

Main Methods:

• Development of a dynamical model based on "contact clusters" representing correlated protein contacts.
• Extensive molecular dynamics (MD) simulations (∼500 μs) of a photoswitchable PDZ3 domain.
• Monitoring of photoinduced allosteric transitions and analysis of contact cluster dynamics.

Main Results:

• The model demonstrates allostery as a multistep process involving cooperative contact changes within and between "contact clusters".
• Rigid secondary structures were identified as key mediators for communication between distant clusters.
• MD simulations successfully captured the time evolution of structural reorganization and ligand effects on nonlocal coupling.
• Simulated dynamics from nanoseconds to microseconds closely matched experimentally measured timescales.

Conclusions:

• The "contact cluster" model provides a robust framework for understanding allosteric communication dynamics.
• Allosteric regulation is mediated by communicating networks of correlated contacts facilitated by protein structure.
• The findings offer insights into the fundamental mechanisms of signal transduction in proteins.