Combined MD and QM/MM Investigations of Hydride Reduction of 5α-Dihydrotestosterone Catalyzed by Human 3α-Hydroxysteroid Dehydrogenase Type 3: Importance of Noncovalent Interactions

3 alpha-Hydroxysteroid dehydrogenase (3 alpha-HSD) is an enzyme that is essential in the regulation of the concentration of 5 alpha-dihydrotestosterone (5 alpha-DHT) in the prostate. It catalyzes the hydride reduction of 5 alpha-DHT to 3 alpha-androstanediol, which activates androgen receptors. Elucidating details about the hydride reduction of 5 alpha-DHT by 3 alpha-HSD and the environment around the active site of the enzyme could lead to the development of effective drugs for the treatment of prostate cancer. In this study, the X-ray crystal structure of human 3 alpha-HSD type 3 was comprehensively evaluated. Moreover, molecular dynamics (MD) simulations and hybrid ONIOM-type quantum mechanics/molecular mechanics (QM/MM) calculations were performed using a large QM region (maximum 232 atoms). It was determined that the reaction proceeded in a single step without the formation of an alkoxide ion owing to the direct hydride reduction of the substrate by nicotinamide adenine dinucleotide phosphate (NADPH) and concerted proton transfer by Tyr55 and Lys84. Noncovalent interaction (NCI) analysis highlighted the roles of Tyr216 and Trp227 in 3 alpha-HSD. Specifically, Tyr216 assisted the reaction by pi/pi interactions with the neighboring nicotinamide ring of NADP(H), whereas Trp227 played an important role in recognition of the size of the substrate by CH/pi interactions.

Automated summary

3α-HSD enzyme plays a crucial role in regulating the concentration of 5α-DHT in the prostate. Understanding the mechanism of 5α-DHT hydride reduction by 3α-HSD could lead to the development of effective drugs for prostate cancer treatment. The study conducted comprehensive evaluation of human 3α-HSD type 3 crystal structure, revealing key interactions and mechanisms involved in the reaction process.