Journal article
Structural Insights into Hearing Loss Genetics from Polarizable Protein Repacking
Biophysical journal, Vol.117(3), pp.602-612
08/06/2019
DOI: 10.1016/j.bpj.2019.06.030
PMID: 31327459
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 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.
Details
- Title: Subtitle
- Structural Insights into Hearing Loss Genetics from Polarizable Protein Repacking
- Creators
- Mallory R Tollefson - University of IowaJacob M Litman - University of IowaGuowei Qi - University of IowaClaire E O’Connell - University of IowaMatthew J Wipfler - University of IowaRobert J Marini - University of Iowa Hospitals and ClinicsHernan V Bernabe - University of IowaWilliam T.A Tollefson - University of IowaTerry A Braun - University of IowaThomas L Casavant - University of IowaRichard J.H Smith - University of Iowa Hospitals and ClinicsMichael J Schnieders - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Biophysical journal, Vol.117(3), pp.602-612
- DOI
- 10.1016/j.bpj.2019.06.030
- PMID
- 31327459
- NLM abbreviation
- Biophys J
- ISSN
- 0006-3495
- eISSN
- 1542-0086
- Publisher
- Elsevier Inc
- Grant note
- name: NSF, award: 000390183; name: NIH/Center for Biocatalysis and Bioprocessing, award: T32 GM0008365; name: University of Iowa Presidential Graduate Research Fellowship; name: NSF, award: CHE-1751688; name: NIH, award: DC012049; name: The University of Iowa Center for Research by Undergraduates
- Language
- English
- Date published
- 08/06/2019
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Electrical and Computer Engineering; Molecular Physiology and Biophysics; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Biochemistry and Molecular Biology; Chemical and Biochemical Engineering; Otolaryngology; Internal Medicine
- Record Identifier
- 9984196998802771
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