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PDZ domains are typical examples of binding motifs mediating the formation ofprotein-protein assemblies in many different cells. A quantitativecharacterization of the mechanisms intertwining structure, chemistry anddynamics with the PDZ function represent a challenge in molecular biology. Herewe investigated the influence of native state topology on the thermodynamicsand the dissociation kinetics for a complex PDZ-peptide via Molecular Dynamicssimulations based on a coarse-grained description of PDZ domains. Ournative-centric approach neglects chemical details but incorporates the basicstructural information to reproduce the protein functional dynamics as itcouples to the binding. We found that at physiological temperatures theunbinding of a peptide from the PDZ domain becomes increasingly diffusiverather than thermally activated, as a consequence of the significant reductionof the free energy barrier with temperature. In turn, this results in asignificant slowing down of the process of two orders of magnitude with respectto the conventional Arrhenius extrapolation from low temperature calculations.Finally, a detailed analysis of a typical unbinding event based on the rupturetimes of single peptide-PDZ contacts allows to shed further light on thedissociation mechanism and to elaborate a coherent picture of the relationbetween function and dynamics in PDZ domains.

Diffusion-limited unbinding of small peptides from PDZ domains