Allosteric Communication Networks in Proteins Revealed through Pocket Crosstalk Analysis,ACS Central Science

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Allosteric Communication Networks in Proteins Revealed through Pocket Crosstalk Analysis
ACS Central Science ( IF 12.7 ) Pub Date : 2017-08-10 00:00:00 , DOI: 10.1021/acscentsci.7b00211
Giuseppina La Sala ₁ , Sergio Decherchi _{2,

3} , Marco De Vivo _{1,

4} , Walter Rocchia ₂

Affiliation

The detection and characterization of binding pockets and allosteric communication in proteins is crucial for studying biological regulation and performing drug design. Nowadays, ever-longer molecular dynamics (MD) simulations are routinely used to investigate the spatiotemporal evolution of proteins. Yet, there is no computational tool that can automatically detect all the pockets and potential allosteric communication networks along these extended MD simulations. Here, we use a novel and fully automated algorithm that examines pocket formation, dynamics, and allosteric communication embedded in microsecond-long MD simulations of three pharmaceutically relevant proteins, namely, PNP, A2A, and Abl kinase. This dynamic analysis uses pocket crosstalk, defined as the temporal exchange of atoms between adjacent pockets, along the MD trajectories as a fingerprint of hidden allosteric communication networks. Importantly, this study indicates that dynamic pocket crosstalk analysis provides new mechanistic understandings on allosteric communication networks, enriching the available experimental data. Thus, our results suggest the prospective use of this unprecedented dynamic analysis to characterize transient binding pockets for structure-based drug design.

中文翻译：

通过袖珍串扰分析揭示蛋白质中的变构通讯网络

蛋白质中结合口袋和变构通讯的检测和表征对于研究生物学调控和进行药物设计至关重要。如今，常规地使用越来越长的分子动力学（MD）模拟来研究蛋白质的时空演化。但是，没有计算工具可以沿着这些扩展的MD模拟自动检测所有口袋和潜在的变构通讯网络。在这里，我们使用一种新颖的，全自动的算法，该算法可检查微囊长的三种药物相关蛋白（即PNP，A2A和Abl激酶）的MD模拟中嵌入的口袋形成，动力学和变构通讯。这种动态分析使用的是袋状串扰，其定义为相邻袋间的原子在时间上的交换，沿着MD轨迹作为隐藏的变构通讯网络的指纹。重要的是，这项研究表明动态袖珍串扰分析为变构通讯网络提供了新的机理理解，丰富了可用的实验数据。因此，我们的结果表明，这种前所未见的动态分析有望用于基于结构的药物设计中的瞬时结合口袋的表征。

更新日期：2017-08-10

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