Binding modes and conformational changes of FK506-binding protein 51 induced by inhibitor bindings: insight into molecular mechanisms based on multiple simulation technologies

The FK506-binding protein 51 (FKBP51) is a cochaperone that modulates the signal transduction of steroid hormone receptors and has been involved in prostate cancer, indicating that FKBP51 is an attractive target of drug design curing the related cancers. In this work, multiple short molecular dynamics (MSMD) simulations are combined with MM-GBSA method to investigate binding modes of inhibitors 3JP, 3JR and 3JQ to FKBP51. The results show that the substitutions of diols (R)-19 and (S)-19 at the R position of 3JP strengthen binding of 3JR and 3JQ to FKBP51. Principal component (PC) analysis performed on the equilibrated MSMD trajectories suggests that three inhibitor bindings produce significant effect on dynamics behavior and conformational changes of the loops L1, L2 and the domain β-L-α-L-β in FKBP51. The calculations of residue-based free energy decomposition not only recognize the hot interaction spot of inhibitors with FKBP51, but also display that the substitutions of diols (R)-19 and (S)-19 at the R position of 3JP play significant role in stronger binding of 3JR and 3JQ to FKBP51 than 3JP. This work is expected to provide theoretical hints and molecular mechanism for design of highly efficient inhibitors toward FKBP51.