Molecular mechanism of R-bicalutamide switching from androgen receptor antagonist to agonist induced by amino acid mutations using molecular dynamics simulations and free energy calculation

R-bicalutamide, a first generation antiandrogen, was used to treat prostate cancer for decades. Although it is very effective at the beginning, resistance appears after 2–3 years of treatment. Mutation of androgen receptor (AR) is considered a main reason for drug resistance. It is reported that AR W741C, W741L, W741C_T877A, T877A, F876L, F876L_T877A and L701H mutations can convert R-bicalutamide from AR antagonist to agonist, but the switching mechanisms are not clear. In this study, molecular dynamics simulations and molecular mechanics generalized Born surface area (MM-GBSA) calculations were performed to analyze the interaction mechanisms between R-bicalutamide and wild type/mutant ARs. The results indicate that helix H12, which lies on the top of AR LBD like a cover, plays a vital role in R-bicalutamide binding. When interacting with AR, the B-ring of R-bicalutamide pushes H12 aside, distorting the coactivator binding site (AF2) resulting in the inactivation of transcription. Several residue mutations appear to enlarge the distance between the B-ring of R-bicalutamide and H12, reducing steric clash, which is conducive to a closed H12 conformation, leading to the formation of the coactivator binding site AF2 and increased transcription. Hydrogen bond and per-residue free energy decomposition analyses are also investigated to explore the interacting mechanisms, and M895 is found to be a key residue in the antagonist mechanism. The obtained molecular mechanisms will aid rational screening and design of novel AR antagonists, even to mutant AR.