Dynamics-based community analysis and perturbation response scanning of allosteric interaction networks in the TRAP1...

Allosteric interactions of the Hsp90 chaperones with cochaperones and diverse protein clients can often exhibit distinct asymmetric features that determine regulatory mechanisms and cellular functions in many signaling networks. The recent crystal structures of the mitochondrial Hsp90 isoform TRAP1 in complexes with ATP analogs have provided first evidence of significant asymmetry in the closed dimerized state that triggers independent activity of the chaperone protomers, whereby preferential hydrolysis of the buckled protomer is followed by conformational flipping between protomers and hydrolysis of the second protomer. Despite significant insights in structural characterizations of the TRAP1 chaperone, the atomistic details and mechanics of allosteric interactions that couple sequential ATP hydrolysis with asymmetric conformational switching in the TRAP1 protomers remain largely unknown. In this work, we explored atomistic and coarse-grained simulations of the TRAP1 dimer structures in combination with the ensemble-based network modeling and perturbation response scanning of residue interaction networks to probe salient features underlying allosteric signaling mechanism. This study has revealed that key effector sites that orchestrate allosteric interactions occupy the ATP binding region and N-terminal interface of the buckled protomer, whereas the main sensors of allosteric signals that drive functional conformational changes during ATPase cycle are consolidated near the client binding region of the straight protomer, channeling the energy of ATP hydrolysis for client remodeling. The community decomposition analysis of the interaction networks and reconstruction of allosteric communication pathways in the TRAP1 structures have quantified mechanism of allosteric regulation, revealing control points and interactions that coordinate asymmetric switching during ATP hydrolysis.