Computational Modeling of Allosteric Regulation in the Hsp90 Chaperones: A Statistical Ensemble Analysis of Protein Structure Networks and Allosteric Communications

Abstract

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.

Author Summary

Functional versatility and structural adaptability of the Hsp90 chaperones are regulated by allosteric interactions that allow for diverse functions including modulation of ATP hydrolysis and binding with cochaperones and client proteins. By integrating molecular simulations and network-based approaches we have characterized conformational dynamics and allosteric interactions in different functional forms of Hsp90. The network centrality analysis and structural mapping of allosteric communications have revealed a small-world organization of the interaction network that is mediated by functionally important residues of the Hsp90 activity. We have found that effective allosteric communications in the Hsp90 chaperone may be provided by structurally stable residues that exhibit high centrality properties. Nucleotide-specific rewiring of the network topology and assortative organization of functional residues may protect the active form of the chaperone from random perturbations and detrimental mutations. These results have confirmed that allosteric interactions in the Hsp90 chaperone may be determined by a small-world network of functional residues that can regulate the network efficiency and resiliency by modulating the statistical ensemble of communication pathways in response to functional requirements of the ATPase cycle.