Department of Biomedical Engineering, University of Iowa, Iowa City, Iowa; Molecular Otolaryngology & Renal Research Laboratories, Department of Otolaryngology-Head and Neck Surgery, University of Iowa Hospitals and Clinics, Iowa City, Iowa.
Department of Biochemistry, University of Iowa, Iowa City, Iowa.
Biophys J. 2019 Aug 6;117(3):602-612. doi: 10.1016/j.bpj.2019.06.030. Epub 2019 Jul 3.
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.
听力损失与 152 个基因中的约 8100 个突变有关，而这些基因的编码区域中存在超过 60000 个错义变体。这些变体中的大多数被归类为“意义不明的变体”，以反映我们无法将观察到的氨基酸变化归因于表型效应。生物物理模拟是一种有前途的致病性信息来源，尽管由于实验数据的限制和/或与模板的远同源性，输入的蛋白质结构通常存在缺陷。在这里，我们结合了可极化原子多极优化生物分子应用能量的力场、多体优化理论和图形处理单元加速，对所有与耳聋相关的蛋白质进行了重新组装，从而将平均结构 MolProbity 评分从 2.2 提高到 1.0。然后，我们使用这些优化的野生型模型为耳聋变异数据库中的错义变异体创建了超过 60000 个结构，这些结构正在被纳入耳聋变异数据库，以告知耳聋的致病性预测。最后，这项工作表明，先进的可极化原子多极力场效率足够高，可以重新组装整个人类蛋白质组。
