Central to Hsp90’s biological function is its ability to interconvert between various conformational states. Drug targeting of Hsp90’s regulatory mechanisms, including its modulation by cochaperone association, presents as an attractive therapeutic strategy for Hsp90 associated pathologies. In this study, we utilized homology modeling techniques to calculate full-length structures of human Hsp90α in closed and partially open conformations and used these structures as a basis for several molecular dynamics based analyses aimed at elucidating allosteric mechanisms and modulation sites in human Hsp90α. Atomistic simulations demonstrated that bound adenosine triphosphate (ATP) stabilizes the dimer by “tensing” each protomer, while adenosine diphosphate (ADP) and apo configurations “relax” the complex by increasing global flexibility, the former case resulting in a fully open “v-like” conformation. Dynamic residue network analysis revealed regions of the protein involved in intraprotein communication and identified several key communication hubs that correlate with known functional sites. Pairwise comparison of betweenness centrality, shortest path, and residue fluctuations revealed that a proportional relationship exists between the latter two measurables and an inverse relationship between these two and betweenness centrality. This analysis showed how protein flexibility, degree of compactness, and the distance cutoff used for network construction influence the correlations between these metrics. These findings are novel and suggest shortest path and betweenness centrality to be more relevant quantities to follow for detecting functional residues in proteins compared to residue fluctuations. Perturbation response scanning analysis identified several potential residue sites capable of modulating conformational change in favor of interstate conversion. For the ATP-bound open conformation, these sites were found to overlap with known Aha1 and client binding sites, demonstrating how naturally occurring forces associated with cofactor binding could allosterically modulate conformational dynamics.

中文翻译：

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人类Hsp90α构象动力学的变构调制。

Hsp90生物学功能的核心是其在各种构象状态之间相互转换的能力。Hsp90调节机制的药物靶向，包括其甲壳伴侣结合的调节，是Hsp90相关病理学的一种有吸引力的治疗策略。在这项研究中，我们利用同源性建模技术来计算人Hsp90α在闭合和部分开放构象中的全长结构，并将这些结构用作基于分子动力学的分析的基础，这些分析旨在阐明人Hsp90α的变构机理和调控位点。原子模拟表明，结合的三磷酸腺苷（ATP）通过“张紧”每个protomer来稳定二聚体，而二磷酸腺苷（ADP）和apo构型则通过增加全局灵活性来“放松”复合物，前一种情况导致完全开放的“ v形”构象。动态残基网络分析揭示了参与蛋白内通讯的蛋白质区域，并确定了与已知功能位点相关的几个关键通讯中心。成对比较中心性，最短路径和残基波动表明，后两个可测度之间存在比例关系，而这两个和中间性之间存在反比关系。该分析表明蛋白质柔韧性，紧密度和用于网络构建的距离截止如何影响这些指标之间的相关性。这些发现是新颖的，暗示与残基波动相比，最短的路径和中间性中心性是检测蛋白质中功能性残基要遵循的更相关的量。扰动响应扫描分析确定了几个潜在的残基位点，这些位点能够调节构象变化，有利于州际转换。对于ATP结合的开放构象，发现这些位点与已知的Aha1和客户结合位点重叠，表明与辅因子结合相关的自然发生力如何变构地调节构象动力学。