Role of Terahertz (THz) Fluctuations in the Allosteric Properties of the PDZ Domains

With the aim of investigating the relationship between the fast
fluctuations of proteins and their allosteric behavior, we perform
molecular dynamics simulations of two model PDZ domains with
differential allosteric responses. We focus on protein dynamics in the
THz regime (0.1-3 THz) as opposed to lower frequencies. By
characterizing the dynamic modulation of the protein backbone induced by
ligand binding in terms of single residue and pairwise distance
fluctuations, we identify a response nucleus modulated by the ligand
that is visible only at THz frequencies. The residues of this nucleus
undergo a significant stiffening and an increase in mutual coordination
upon binding. Additionally, we find that the dynamic modulation is
significantly more intense for the side chains, where it is also
redistributed to distal regions not immediately in contact with the
ligand allowing us to better define the response nucleus at THz
frequencies. The overlap between the known allosterically responding
residues of the investigated PDZ domains and the modulated region
highhghted here suggests that fast THz dynamics could play a role in
allosteric mechanisms.