FIRST PRINCIPLES CALCULATION OF THE ACTIVITY OF CYTOCHROME-P450

The cytochrome P450 superfamily of enzymes is of enormous interest in the biological sciences due to the wide range of endogenous and xenobi otic compounds which it metabolises, including many drugs. We describe the use of first principles quantum mechanical modeling techniques, b ased on density functional theory, to determine the outcome of interac tions between an enzyme and a number of compounds. Specifically, we ca lculate the spin state of an Fe3+ ion present in a haem moiety at the active site of these enzymes. The spin state of this ion indicates if the catalytic reaction will proceed. The computational results obtaine d compare favorably with experimental data. Only the principle compone nts of the active site of the enzyme an included in the computational models, demonstrating that only a small fragment of the protein needs to be included in the models in order to accurately reproduce this asp ect of the enzymes' function. These results open the way for further i nvestigation of this superfamily of enzymes using the methods detailed in this paper.