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POSSIBLE PATHWAY(S) OF TESTOSTERONE EGRESS FROM THE ACTIVE SITE OF CYTOCHROME P450 2B1: A STEERED MOLECULAR DYNAMICS SIMULATION

Center for Drug Discovery and Design, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Graduate School of the Chinese Academy of Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China (W.L., H.L., F.G., X.L., J.S., H.J.); Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas (J.R.H.); Department of Medicinal Chemistry, University of Kansas, Lawrence, Kansas (E.E.S.); and School of Pharmacy, East China University of Science and Technology, Shanghai, China (H.J.)

To probe the possible substrate exit channel(s) in cytochrome P450 (P450) 2B1 and to clarify the role of residues previously identified by site-directed mutagenesis, a homology model was constructed based on the X-ray crystal structure of a P450 2B4-inhibitor complex. Testosterone was docked into the active site of P450 2B1 and was then pulled out through three putative channels using steered molecular dynamics simulations. The results indicated that of the three channels, the "solvent channel," lined by helices E, F, and I and the ß3 hairpin, required the largest rupture force and backbone motion, which rendered it unlikely as an exit route. The relatively small rupture forces and backbone motions for the other two channels suggested them as possible candidates for testosterone passage. The opening of channel 1, located between helices G and I and the B'-C loop, is characterized by rotation of the aromatic ring of Phe297 together with a bending of the B'-C loop. The opening of channel 2, penetrating through the B'-C loop/B' helix, is achieved by an expansion of this region and a small displacement of the backbone. Interestingly, during the egress of testosterone along channel 1, Phe297 and Phe108 appear to act as two clamps to stabilize testosterone binding and prevent it from leaving the active site. Phe115 acts as a gatekeeper for channel 2. These results are in agreement with previous site-directed mutagenesis experiments.

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