Allosteric Modulation of Human Hsp90α Conformational Dynamics

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.

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