Structural dynamics is a determinant of the functional significance of missense variants.
Structural dynamics is a determinant of the functional significance of missense variants.
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DOI：
10.1073/pnas.1715896115
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发表时间：
2018-04-17
影响因子：
11.1
通讯作者：
Bahar I
中科院分区：
文献类型：
--
作者：
Ponzoni L;Bahar I
区分临床相关突变与中性突变在精准医学和药物基因组学中至关重要。我们的研究表明，目前的计算预测的致病性，主要是基于序列保守性的分析，可以通过考虑点突变引起的蛋白质结构动力学的变化来改善。我们介绍并证明了一个分类器，利用弹性网络模型的结构动力学的有效评估的效用。准确评估点突变对蛋白质功能的影响对于评估许多遗传性疾病和癌症类型的发生和预后至关重要。目前，已经开发了大量的计算工具用于致病性预测。两种主要类型的数据用于此目的：序列保守/进化和结构特性。在这里，我们以系统的方式证明了错义变体的功能影响的另一个决定因素是蛋白质的结构动力学。通过考虑突变的动态背景和影响，在致病性预测中显示出可测量的改进。我们的研究表明，这里介绍的一类动态描述符可以与现有的功能结合使用，不仅可以提高预测精度的影响的变体对生物功能，而且还可以深入了解的物理基础的错义变体的影响。
Discrimination of clinically relevant mutations from neutral mutations is of paramount importance in precision medicine and pharmacogenomics. Our study shows that current computational predictions of pathogenicity, mostly based on analysis of sequence conservation, may be improved by considering the changes in the structural dynamics of the protein due to point mutations. We introduce and demonstrate the utility of a classifier that takes advantage of efficient evaluation of structural dynamics by elastic network models. Accurate evaluation of the effect of point mutations on protein function is essential to assessing the genesis and prognosis of many inherited diseases and cancer types. Currently, a wealth of computational tools has been developed for pathogenicity prediction. Two major types of data are used to this aim: sequence conservation/evolution and structural properties. Here, we demonstrate in a systematic way that another determinant of the functional impact of missense variants is the protein’s structural dynamics. Measurable improvement is shown in pathogenicity prediction by taking into consideration the dynamical context and implications of the mutation. Our study suggests that the class of dynamics descriptors introduced here may be used in conjunction with existing features to not only increase the prediction accuracy of the impact of variants on biological function, but also gain insight into the physical basis of the effect of missense variants.
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影响因子：
4.3
作者：
Bendl J;Stourac J;Salanda O;Pavelka A;Wieben ED;Zendulka J;Brezovsky J;Damborsky J
通讯作者：
Damborsky J
影响因子：
3.4
作者：
Eyal, Eran;Bahar, Ivet
通讯作者：
Bahar, Ivet
影响因子：
4.5
作者：
LaRusch J;Jung J;General IJ;Lewis MD;Park HW;Brand RE;Gelrud A;Anderson MA;Banks PA;Conwell D;Lawrence C;Romagnuolo J;Baillie J;Alkaade S;Cote G;Gardner TB;Amann ST;Slivka A;Sandhu B;Aloe A;Kienholz ML;Yadav D;Barmada MM;Bahar I;Lee MG;Whitcomb DC;North American Pancreatitis Study Group
通讯作者：
North American Pancreatitis Study Group
影响因子：
30.8
作者：
Kircher, Martin;Witten, Daniela M.;Jain, Preti;O'Roak, Brian J.;Cooper, Gregory M.;Shendure, Jay
通讯作者：
Shendure, Jay
影响因子：
5.8
作者：
Mottaz, Anais;David, Fabrice P. A.;Yip, Yum L.
通讯作者：
Yip, Yum L.