Investigating Protein–Protein Allosteric Network using Current‐Flow Scheme,Journal of Computational Chemistry

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Investigating Protein–Protein Allosteric Network using Current‐Flow Scheme
Journal of Computational Chemistry ( IF 3.4 ) Pub Date : 2019-11-28 , DOI: 10.1002/jcc.26108
Wesley M Botello-Smith ₁ , Yun Luo ₁

Affiliation

Protein dynamic network analysis provides a powerful tool for investigating protein allosteric regulation. We recently developed a current‐flow betweenness scheme for protein network analysis and demonstrated that this method, that is, using current‐flow betweenness as edge weights, is more appropriate and more robust for investigating the signal transmission between two predefined protein residues or domains as compared with direct usage of correlation scores as edge weights. Here we seek to expand the current‐flow scheme to study allosteric regulations involving protein–protein binding. Specifically, we investigated three gain‐of‐function mutations located at the binding interface of ALK2 (also known as ACVR1) kinase and its inhibitory protein FKBP12. We first searched for the optimal smoothing function for contact network construction and then calculated the subnetwork between FKBP12 protein and the kinase ATP binding site using current‐flow betweenness. By comparing the networks between the wild‐type and three mutants, we have identified statistically significant changes in the protein–protein networks that are common among all three mutants that allosterically shift the kinase toward a catalytically competent configuration. © 2019 Wiley Periodicals, Inc.

中文翻译：

使用电流流动方案研究蛋白质-蛋白质变构网络

蛋白质动态网络分析为研究蛋白质变构调节提供了强大的工具。我们最近开发了一种用于蛋白质网络分析的电流介数方案，并证明了这种方法，即使用电流介数作为边缘权重，对于研究两个预定义的蛋白质残基或结构域之间的信号传输更合适、更稳健与直接使用相关分数作为边缘权重相比。在这里，我们寻求扩展电流方案以研究涉及蛋白质 - 蛋白质结合的变构调节。具体而言，我们研究了位于 ALK2（也称为 ACVR1）激酶及其抑制蛋白 FKBP12 结合界面的三个功能获得性突变。我们首先搜索接触网络构建的最佳平滑函数，然后使用电流介数计算 FKBP12 蛋白与激酶 ATP 结合位点之间的子网络。通过比较野生型和三个突变体之间的网络，我们已经确定了蛋白质-蛋白质网络的统计学显着变化，这些变化在所有三个突变体中是常见的，这些变化将激酶变构地转变为具有催化能力的构型。© 2019 威利期刊公司。我们已经确定了蛋白质 - 蛋白质网络的统计学显着变化，这些变化在所有三种突变体中都很常见，这些突变体将激酶变构地转变为具有催化能力的构型。© 2019 威利期刊公司。我们已经确定了蛋白质 - 蛋白质网络的统计学显着变化，这些变化在所有三种突变体中都很常见，这些突变体将激酶变构地转变为具有催化能力的构型。© 2019 威利期刊公司。

更新日期：2019-11-28

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