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首页> 外文期刊>PLoS Computational Biology >Computational Modeling of Allosteric Regulation in the Hsp90 Chaperones: A Statistical Ensemble Analysis of Protein Structure Networks and Allosteric Communications
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Computational Modeling of Allosteric Regulation in the Hsp90 Chaperones: A Statistical Ensemble Analysis of Protein Structure Networks and Allosteric Communications

机译：Hsp90伴侣的变构调节的计算模型：蛋白质结构网络和变构通讯的统计合计分析。

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A fundamental role of the Hsp90 chaperone in regulating functional activity of diverse protein clients is essential for the integrity of signaling networks. In this work we have combined biophysical simulations of the Hsp90 crystal structures with the protein structure network analysis to characterize the statistical ensemble of allosteric interaction networks and communication pathways in the Hsp90 chaperones. We have found that principal structurally stable communities could be preserved during dynamic changes in the conformational ensemble. The dominant contribution of the inter-domain rigidity to the interaction networks has emerged as a common factor responsible for the thermodynamic stability of the active chaperone form during the ATPase cycle. Structural stability analysis using force constant profiling of the inter-residue fluctuation distances has identified a network of conserved structurally rigid residues that could serve as global mediating sites of allosteric communication. Mapping of the conformational landscape with the network centrality parameters has demonstrated that stable communities and mediating residues may act concertedly with the shifts in the conformational equilibrium and could describe the majority of functionally significant chaperone residues. The network analysis has revealed a relationship between structural stability, global centrality and functional significance of hotspot residues involved in chaperone regulation. We have found that allosteric interactions in the Hsp90 chaperone may be mediated by modules of structurally stable residues that display high betweenness in the global interaction network. The results of this study have suggested that allosteric interactions in the Hsp90 chaperone may operate via a mechanism that combines rapid and efficient communication by a single optimal pathway of structurally rigid residues and more robust signal transmission using an ensemble of suboptimal multiple communication routes. This may be a universal requirement encoded in protein structures to balance the inherent tension between resilience and efficiency of the residue interaction networks.
机译：Hsp90伴侣在调节各种蛋白质客户的功能活性中的基本作用对于信号网络的完整性至关重要。在这项工作中，我们将Hsp90晶体结构的生物物理模拟与蛋白质结构网络分析相结合，以表征Hsp90分子伴侣中的变构相互作用网络和通信途径的统计整体。我们发现在构象集合的动态变化过程中可以保留主要的结构稳定的群落。域间刚度对相互作用网络的主要贡献已经成为引起活性伴侣形式在ATPase循环中热力学稳定性的共同因素。使用残基间波动距离的力常数分析进行结构稳定性分析，已确定了一个保守的结构刚性残基网络，可以用作变构通讯的整体中介位。构象景观与网络中心性参数的映射表明，稳定的群落和中介残基可能与构象平衡的变化协调一致，并且可以描述大多数功能上重要的伴侣残基。网络分析揭示了伴侣伴侣调控中热点残基的结构稳定性，整体中心性和功能重要性之间的关系。我们已经发现，Hsp90伴侣中的变构相互作用可能是由结构稳定的残基模块介导的，该模块在全球相互作用网络中显示出很高的介导性。这项研究的结果表明，Hsp90分子伴侣中的变构相互作用可能通过一种机制进行，该机制结合了通过结构刚性残基的单个最佳途径进行快速有效的通讯，以及使用次优的多种通讯途径进行的更鲁棒的信号传递。这可能是编码在蛋白质结构中的通用要求，以平衡残基相互作用网络的弹性和效率之间的固有张力。

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