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Possible Pathway(s) of Metyrapone Egress from the Active Site of Cytochrome P450 3A4: A Molecular Dynamics Simulation

School of Pharmacy, East China University of Science and Technology, Shanghai, China (W.L., Y.T., H.J.); 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., X.L., W.Z., H.J.); and Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas (J.R.H.)

To identify a possible pathway(s) for metyrapone egress from the active site of P450 3A4, a 5-ns conventional molecular dynamics simulation followed by steered molecular dynamics simulations was performed on the complex with metyrapone. The steered molecular dynamics simulations showed that metyrapone egress via channel 1, threading through the B-C loop, only required a relatively small rupture force and small displacement of residues, whereas egress via the third channel, between helix I and helices F' and G', required a relatively large force and perturbation of helices I, B', and C. The conventional dynamics simulation indicated that channel 2, located between the ß1 sheet, B-B' loop, and F'-G' region, is closed because of the movement of residues in the mouth of this channel. The findings suggest that channel 1 can be used for metyrapone egress, whereas both channel 2 and channel 3 have a low probability of serving as an exit channel for metyrapone. In addition, residues F108 and I120 appear to act as two gatekeepers to prevent the inhibitor from leaving the active site. These results are in agreement with previous site-directed mutagenesis experiments.