Density functional theory study on the C-H bond activation of alkane by cytochrome P450

The C-H bond activation of alkane by compound I of cytochrome P450 is studied with density functional theory calculations, particularly with respect to the kinetic isotope effects (KIEs). The transition state for the C-H bond dissociation involves a linear array of C-H-O(Fe), which leads to an Fe-OH intermediate and an alkyl radical species. The "oxene insertion" mechanism is unlikely to occur in P450-mediated hydroxylation. The KIE values calculated with transition state theory for the H/D abstraction in C2H6/CH2DCH3, C2H6/CD3CH3, and C2H6/C2D6 are 7, 11, and 14, respectively, at 300 K. Thus, molecular parts that have no direct relevance to the abstraction reaction significantly affect the KIEs. (C) 2002 Elsevier Science B.V. All rights reserved.