Domino Effect in Allosteric Signaling of Peptide Binding

• Published in: Journal of molecular biology 2022-09, Vol.434 (17), p.167661-167661, Article 167661
• Main Authors: Vargas-Rosales, Pablo Andrés, Caflisch, Amedeo
• Format: Article
• Language: English
• Subjects: free energy profile; isoleucine; molecular biology; molecular dynamics; mutants; optimal reaction coordinate; PDZ3 domain; peptides; signal transduction; slowest-relaxation eigenvector
• ISSN: 0022-2836; 1089-8638
• DOI: 10.1016/j.jmb.2022.167661

[Display omitted] •Elucidation of allosteric signaling pathway from molecular dynamics simulations.•Unsupervised, data-driven analysis of peptide binding to a PDZ domain.•Use of optimal reaction coordinate framework for enhancing sampling of simulations.•Residue-level reconstruction of the transfer of allosteric signal. While being a thoroughly studied model of dynamic allostery in a small protein, the pathway of signal transduction in the PDZ3 domain has not been fully determined. Here, we investigate peptide binding to the PDZ3 domain by conventional and fully data-driven analyses of molecular dynamics simulations. First, we identify isoleucine 37 as a key residue by widely used computational procedures such as cross-correlation and community network analysis. Simulations of the Ile37Ala mutant show disruption of the coordinated movements of spatially close regular elements of secondary structure. Then, we employ a recently developed unsupervised, data-driven procedure to determine an optimized reaction coordinate (slowest-relaxation eigenvector) of peptide binding. We use this reaction coordinate to improve sampling by restarting additional simulations from the transition state region. Significant differences in the distributions of some of the pairwise residue distances in the bound and unbound states emerge from the projection onto the optimized reaction coordinate. The unsupervised analysis shows that allosteric signaling is transduced from the β2 strand, which forms part of the peptide binding site, to the spatially adjacent β3 and β4 strands, and from there to the α3 helix. The domino-like transmission of a (peptide binding) signal along β strands and α helices that are close in three-dimensional space is likely to be a general mechanism of allostery in single-domain proteins.