Diffusion-limited unbinding of small peptides from PDZ domains

TL;DR

This study uses coarse-grained molecular dynamics to explore how native state topology influences peptide unbinding from PDZ domains, revealing a transition from thermally activated to diffusive unbinding at physiological temperatures.

Contribution

It demonstrates that unbinding becomes diffusion-limited at physiological temperatures, highlighting the role of native topology in PDZ-peptide dissociation dynamics.

Findings

Unbinding slows down by two orders of magnitude at physiological temperatures.

Unbinding transitions from thermally activated to diffusive process with increasing temperature.

Analysis of rupture times clarifies the dissociation mechanism in PDZ domains.

Abstract

PDZ domains are typical examples of binding motifs mediating the formation of protein-protein assemblies in many different cells. A quantitative characterization of the mechanisms intertwining structure, chemistry and dynamics with the PDZ function represent a challenge in molecular biology. Here we investigated the influence of native state topology on the thermodynamics and the dissociation kinetics for a complex PDZ-peptide via Molecular Dynamics simulations based on a coarse-grained description of PDZ domains. Our native-centric approach neglects chemical details but incorporates the basic structural information to reproduce the protein functional dynamics as it couples to the binding. We found that at physiological temperatures the unbinding of a peptide from the PDZ domain becomes increasingly diffusive rather than thermally activated, as a consequence of the significant reduction of the free energy barrier with temperature. In turn, this results in a significant slowing down of the process of two orders of magnitude with respect to the conventional Arrhenius extrapolation from low temperature calculations. Finally, a detailed analysis of a typical unbinding event based on the rupture times of single peptide-PDZ contacts allows to shed further light on the dissociation mechanism and to elaborate a coherent picture of the relation between function and dynamics in PDZ domains.