Identifying Allosteric Hotspots with Dynamics: Application to Inter- and Intra-species Conservation.
Identifying Allosteric Hotspots with Dynamics: Application to Inter- and Intra-species Conservation.
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DOI：
10.1016/j.str.2016.03.008
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发表时间：
2016-05-03
期刊：
影响因子：
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通讯作者：
Gerstein M
中科院分区：
文献类型：
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作者：
Clarke D;Sethi A;Li S;Kumar S;Chang RWF;Chen J;Gerstein M
下一代测序计划产生的数据量迅速增长，使人们能够对保护进行比以前更深入的分析。深度测序正在发现选择性限制下的疾病基因座和区域，尽管有时缺乏这种限制的直观生物物理原因。拼读往往可以提供缺失的解释环节。我们使用蛋白质构象变化的模型，通过寻找必要的表面口袋和信息流瓶颈来识别变构残基，我们开发了一种软件工具，使用户能够对自己感兴趣的蛋白质进行这种分析。虽然本质上是3D结构，但我们的分析计算速度很快，从而使我们能够在PDB上运行它，并评估预测的变构残基的一般性质。我们发现，这些往往是保守的不同的进化时间尺度。最后，我们强调变构残基的例子，有助于解释知之甚少的疾病相关的变异。
The rapidly growing volume of data being produced by next-generation sequencing initiatives is enabling more in-depth analyses of conservation than previously possible. Deep sequencing is uncovering disease loci and regions under selective constraint, despite the fact that intuitive biophysical reasons for such constraint are sometimes absent. Allostery may often provide the missing explanatory link. We use models of protein conformational change to identify allosteric residues by finding essential surface pockets and information-flow bottlenecks, and we develop a software tool that enables users to perform this analysis on their own proteins of interest. Though fundamentally 3D-structural in nature, our analysis is computationally fast, thereby allowing us to run it across the PDB and to evaluate general properties of predicted allosteric residues. We find that these tend to be conserved over diverse evolutionary time scales. Finally, we highlight examples of allosteric residues that help explain poorly understood disease-associated variants.