Understanding conformational diversity of heat shock protein 90 (HSP90) and binding features of inhibitors to HSP90 via molecular dynamics simulations.

Heat shock protein 90 (HSP90) is a promising target for treatment of cancer, and inhibitor bindings can generate efficient suppression on tumor in multiple ways. In this work, 140-ns molecular dynamics simulations were performed on six systems. Principal component analysis was subsequently carried out to explore the conformational diversity of HSP90. The results suggest that inhibitor bindings induce large conformational changes of HSP90, which tends to enlarge the volume of the binding pocket to facilitate the entrance of inhibitors. Hierarchical clustering analyses, the calculation of the energy contribution of each atom, and the analyses of hydrogen-bonding interactions were performed. The results indicate that 20 residues in group A of the hierarchical tree are responsible for major contributions, and van der Waals interactions as well as hydrogen-bonding interactions between important residues in HSP90 and key regions of inhibitors are the main force for promoting inhibitor bindings. We expect that this work can provide useful theoretical information for development of efficient inhibitors targeting HSP90.