Diffusion-limited unbinding of small peptides from PDZ domains
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 dissociation kinetics for a PDZ/peptide complex 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 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 2 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 us to shed further light on the dissociation mechanism and to elaborate a coherent picture of the relation between function and dynamics in PDZ domains.