Prediction of allosteric sites and mediating interactions through bond-to-bond propensities
Prediction of allosteric sites and mediating interactions through bond-to-bond propensities
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DOI：
10.1101/056275
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发表时间：
2016-05
影响因子：
16.6
通讯作者：
B. Amor;Michael T. Schaub;S. Yaliraki;Mauricio Barahona
中科院分区：
文献类型：
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作者：
B. Amor;Michael T. Schaub;S. Yaliraki;Mauricio Barahona
变构是生物调节的基本机制，其中在远处位置的分子的结合影响蛋白质的活性位点。变构位点提供了微调蛋白质活性的目标，但我们缺乏预测它们的计算方法。在这里，我们提出了一个有效的图形理论框架来揭示变构相互作用（原子和通信途径强烈耦合到活性位点），而无需先验信息的位置。使用一个原子图与能量加权共价键和弱键，我们定义了一个键到键的倾向量化的非本地效应的瞬时键波动传播通过蛋白质。然后使用分位数回归确定显著的相互作用。我们用三种生物学上重要的蛋白质来验证我们的方法：caspase-1，CheY和h-Ras，正确地预测关键的变构相互作用，其重要性还被100种蛋白质的参考集证实。我们的方法的几乎线性缩放使得它适合于候选变构位点的高通量搜索。变构作用是一种重要的分子机制，在许多细胞过程中起着控制和调节的作用。在这里，作者提出了一种方法，可用于预测变构位点和介导的相互作用，将它们连接到蛋白质的活性位点。
Allostery is a fundamental mechanism of biological regulation, in which binding of a molecule at a distant location affects the active site of a protein. Allosteric sites provide targets to fine-tune protein activity, yet we lack computational methodologies to predict them. Here we present an efficient graph-theoretical framework to reveal allosteric interactions (atoms and communication pathways strongly coupled to the active site) without a priori information of their location. Using an atomistic graph with energy-weighted covalent and weak bonds, we define a bond-to-bond propensity quantifying the non-local effect of instantaneous bond fluctuations propagating through the protein. Significant interactions are then identified using quantile regression. We exemplify our method with three biologically important proteins: caspase-1, CheY, and h-Ras, correctly predicting key allosteric interactions, whose significance is additionally confirmed against a reference set of 100 proteins. The almost-linear scaling of our method renders it suitable for high-throughput searches for candidate allosteric sites. Allostery is a key molecular mechanism underpinning control and modulation in a variety of cellular processes. Here, the authors present a method that can be used to predict allosteric sites and the mediating interactions that connect them to the active site of the protein.