Coevolving residues inform protein dynamics profiles and disease susceptibility of nSNVs

摘要

Author summary Proteins are dynamic machines that undergo atomic fluctuations, side chain rotations, and collective domain movements that are required for biological function. There is, therefore, a need for quantitative metrics that capture the dynamic fluctuations per position to understand the critical role of protein dynamics in shaping biological functions. A limiting factor in incorporating structural dynamics information in the classification of non-synonymous single nucleotide variants (nSNVs) is the limited number of known 3D structures compared to the vast number of available sequences. We have developed a new sequence-based GNM method, termed Seq-GNM, which uses co-evolving amino acid positions based on the multiple sequence alignment of a given query sequence to estimate the thermal motions of C-alpha atoms. In this paper, we have demonstrated that the predicted thermal motions using Seq-GNM are in reasonable agreement with experimental B-factors as well as B-factors computed using 3D crystal structures. We also provide evidence that B-factors predicted by Seq-GNM are capable of distinguishing between disease-associated and neutral nSNVs.