title: Conformational dynamics of nonsynonymous variants at protein interfaces reveals disease association.
abstract: Recent studies have shown that the protein interface sites between individual monomeric units in biological assemblies are enriched in disease-associated non-synonymous single nucleotide variants (nsSNVs). To elucidate the mechanistic underpinning of this observation, we investigated the conformational dynamic properties of protein interface sites through a site-specific structural dynamic flexibility metric (dfi) for 333 multimeric protein assemblies. dfi measures the dynamic resilience of a single residue to perturbations that occurred in the rest of the protein structure and identifies sites contributing the most to functionally critical dynamics. Analysis of dfi profiles of over a thousand positions harboring variation revealed that amino acid residues at interfaces have lower average dfi (31%) than those present at non-interfaces (50%), which means that protein interfaces have less dynamic flexibility. Interestingly, interface sites with disease-associated nsSNVs have significantly lower average dfi (23%) as compared to those of neutral nsSNVs (42%), which directly relates structural dynamics to functional importance. We found that less conserved interface positions show much lower dfi for disease nsSNVs as compared to neutral nsSNVs. In this case, dfi is better as compared to the accessible surface area metric, which is based on the static protein structure. Overall, our proteome-wide conformational dynamic analysis indicates that certain interface sites play a critical role in functionally related dynamics (i.e., those with low dfi values), therefore mutations at those sites are more likely to be associated with disease.
authors.affiliation: Department of Physics, Arizona State University, Tempe, Arizona.
authors.forename: Brandon M
authors.initials: BM
authors.lastname: Butler
authors.forename: Z Nevin
authors.initials: ZN
authors.lastname: Gerek
authors.forename: Sudhir
authors.initials: S
authors.lastname: Kumar
authors.forename: S Banu
authors.initials: SB
authors.lastname: Ozkan
mesh_terms: D030562:Databases, Protein; D004194:Disease / Q000235:genetics*; D006801:Humans; D008958:Models, Molecular; D018583:Pliability; D020641:Polymorphism, Single Nucleotide / Q000235:genetics / Q000502:physiology; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry* / Q000235:genetics*; D040901:Proteomics; D013499:Surface Properties
chemical_list: D011506:Proteins
keywords: conformational dynamics; dynamic flexibility; elastic network model; evolutionary conservation; interfaces; linear response theory; perturbation response scanning; phenotypic prediction; protein-protein interactions; single nucleotide polymorphisms