Structural Insights into Hearing Loss Genetics from Polarizable Protein Repacking

Abstract

Hearing loss is associated with ~8100 mutations in 152 genes, and within the coding regions of these genes are over 60,000 missense variants. The majority of these variants are classified as variants of uncertain significance to reflect our inability to ascribe a phenotypic effect to the observed amino acid change. A promising source of pathogenicity information are atomic resolution simulations, although input protein structures often contain defects due to limitations in experimental data and/or only distant homology to a template. Here we combine the polarizable AMOEBA force field, many-body optimization theory and GPU acceleration to repack all deafness-associated proteins and thereby improve average structure resolution from 2.2 [A] to 1.0 [A] based on assessment with MolProbity. We incorporate these data into the Deafness Variation Database to inform deafness pathogenicity prediction, and show that advanced polarizable force fields could now be used to repack the entire human proteome using the Force Field X software.