Molecular dynamics simulations of CYP2E1.

CYP2E1, as a member of the cytochrome P450s (CYPs) super-family, is in charge of six percent drug metabolism involving a diversity of drugs distinct in structures and chemical properties, such as alcohols, monocyclic compounds (e.g., acetaminophen, benzene, p-nitrophenol), bicyclic heterocycles (e.g., coumarin, caffeine) and even fatty acids. The aromatic molecules form a vital species catalyzed by CYP2E1. To investigate the mechanism of metabolizing a diversity of aromatic molecules, five representative aromatic substrates were selected: (1) benzene, the non-polar simple ring; (2) aniline, the monocyclic substrate with smallest substitution on the phenyl ring; (3) acetaminophen, a large monocyclic substrate with highly active reactivity; (4) chlorzoxazone, and (5) theophylline, the bicyclic substrates with low or high catalytic activities. They were docked into X-ray structure of CYP2E1, after which all-atom molecular dynamics simulations of 5 ns were performed on each model. It was found that the active site interact with the aromatic substrates mainly through π-π stacking, supplied by five hydrophobic phenylalanines in the active site. Our simulations also illustrated the specific movement of different kinds of aromatic substrates in the pocket. Small monocyclic substrates show highly frequent self-rotation and limited translation movement. Substrates with single catalytic position are less movable in the pocket than substrates with multiple products. All these findings are quite useful for understanding the catalytic mechanism of CYP2E1, stimulating novel strategies for conducting further mutagenesis studies for specific drug design.