Dynamic Community Composition Unravels Allosteric Communication in PDZ3

Area of Science:

• Protein dynamics and allosteric regulation
• Computational biophysics
• Molecular interactions

Background:

• The third domain of PSD-95 (PDZ3) is a model system for studying protein-ligand interactions and allosteric communication.
• Previous studies focused on specific structural elements like α-helices (α2 and α3) to explain binding affinity changes in PDZ3 mutants.
• A comprehensive understanding of the dynamical basis for PDZ3 binding selectivity and communication remains elusive.

Purpose of the Study:

• To investigate the molecular basis of PDZ3 binding selectivity and interaction communication using a novel computational approach.
• To analyze the role of conformational dynamics in mediating ligand binding affinity for wild-type and mutant PDZ3 proteins.
• To explore the contribution of distal protein segments to allosteric regulation in protein-ligand complexes.

Main Methods:

• Employed molecular dynamics simulations to generate conformational ensembles for wild-type and mutant PDZ3 proteins with different ligands.
• Utilized graph theory and betweenness centrality to analyze community composition variations within protein dynamics.
• Calculated community composition changes to identify communication pathways and their relation to binding affinity.

Main Results:

• The N-terminus of PDZ3, despite its distance from the ligand, shows a propensity to form communities with the ligand in functional complexes, suggesting distal mediation of binding dynamics.
• The α3 helix acts as a communication hub for the entire protein, connecting various structural segments.
• The α2 helix, lining the binding cavity, frequently separates from the ligand's community, indicating it is not a primary controller of binding but rather influenced by overall protein dynamics coordinated by the N-terminus.

Conclusions:

• Ligand binding fate in PDZ3 is determined by the population of community compositions derived from protein dynamics, even in the absence of significant conformational changes.
• Allosteric communication in PDZ3 is mediated by long-range interactions, particularly involving the N-terminus.
• This study provides a generalized dynamical view of PDZ3 binding selectivity and interaction communication, challenging previous structure-centric interpretations.