Protein dynamics elucidates the phenotypic effects of nsSNVs coupled to functionally critical residues

Biological processes are facilitated largely by protein-protein interactions. Thus, non-synonymous single nucleotide variants (nsSNVs) on interface sites can impair protein function. We investigated the conformational dynamics of interface sites on 333 complexes using a site-specific structural dynamic flexibility metric (DFI). We found interfaces have lower DFI as compared to non-interfaces. Moreover, interface sites with damaging nsSNVs were found to have significantly lower DFI than those with benign nsSNVs, which relates structural dynamics to functional significance. In a new analysis, we considered a small fraction of interface residues known as ``hotspots'', which account for a large portion of the total binding free energy. Hotspots are critical for function, but, importantly, residues that are dynamically coupled to them are also critical. Using a new dynamic measure, functional-DFI (fDFI), on the same set of complexes we considered hotspots as input for f-DFI and estimated their impact on other residues harboring nsSNVs. Based on the f-DFI results, dynamics-based metrics can be useful in assessing phenotypes of residues that are not obvious as critical for function but can be damaging since they are coupled to functionally critical residues.