Ligand-mediated conformation diversity of Hsp90 revealed by GaMD simulations and Markov model

The conformational plasticity of Hsp90 is crucial for understanding its function and drug design. In this study, Gaussian accelerated molecular dynamics (GaMD) simulations followed by Markov model analysis were performed to investigate how the ligands D57, 9QY, and 2GJ affect the in- and out-states of the region between α41 and α42 in Hsp90. Our results showed that binding of these ligands reduces the number of conformational states, especially for 2GJ. Specifically, the conformational transition in Hsp90 bound by D57 in the in-state occurs more readily than that in Hsp90 bound by 9QY in the out-state Hsp90. Principal component analysis (PCA) indicated that the impact of D57 on the conformational fluctuations of α41 in the in-state differs from the effects of 9QY and 2GJ on this helix in the out-state Hsp90. This difference can likely be explained by the variations in network communication caused by these ligands. Furthermore, our analysis of hot spots revealed that the different interactions of D57, 9QY, and 2GJ with residues L48, K58, D93, F183, and T184 are possibly responsible for their distinct conformational plasticity. We hope that this work can provide valuable theoretical insights for designing drugs targeting Hsp90.