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 is biophysical simulation, although input protein structures often contain defects because of limitations in experimental data and/or only distant homology to a template. Here, we combine the polarizable atomic multipole optimized energetics for biomolecular applications force field, many-body optimization theory, and graphical processing unit acceleration to repack all deafness-associated proteins and thereby improve average structure MolProbity score from 2.2 to 1.0. We then used these optimized wild-type models to create over 60,000 structures for missense variants in the Deafness Variation Database, which are being incorporated into the Deafness Variation Database to inform deafness pathogenicity prediction. Finally, this work demonstrates that advanced polarizable atomic multipole force fields are efficient enough to repack the entire human proteome.
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 Å to 1.0 Å 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.
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