Molecular and thermodynamic insights into the conformational transitions of Hsp90.

Hsp90, the most abundant cellular protein, has been implicated in numerous physiological and pathological processes. It controls protein folding and prevents aggregation, but it also plays a role in cancer and neurological disorders, making it an attractive drug target. Experimental efforts have demonstrated its remarkable structural flexibility and conformational complexity, which enable it to accommodate a variety of clients, but have not been able to provide a detailed molecular description of the conformational transitions. In our molecular dynamics simulations, Hsp90 underwent dramatic structural rearrangements into energetically favorable stretched and compact states. The transitions were guided by key electrostatic interactions between specific residues of opposite subunits. Nucleotide-bound structures showed the same conformational flexibility, although ADP and ATP seemed to potentiate these interactions by stabilizing two different closed conformations. Our observations may explain the difference in dynamic behavior observed among Hsp90 homologs, and the atomic resolution of the conformational transitions helps elucidate the complex chaperone machinery.