Abstract
The substrate-free form of P450 c a m (CYP101) has been studied by combined quantum mechanical/molecular mechanical (QM/MM) calculations. The central iron(III) aqua porphyrin complex is treated with density functional theory, while the protein/solvent environment is represented by the CHARMM force field. Calculations with different functionals probe the influence of the amount of exact exchange on the relative energies computed for different spin states. B3LYP/CHARMM computations indicate a doublet ground state consistent with experimental results, with small energetic separations to the quartet and sextet. Optimized doublet geometries are in good agreement with experimental data. Comparisons with analogous calculations on the isolated QM system in the gas phase show that the protein/solvent environment reduces the doublet-quartet and doublet-sextet gaps, favors an upright conformation of the axial water ligand by H-bond interactions within the binding pocket, and lengthens the Fe-S bond while shortening the Fe-O bond. Different protein/ solvent conformations (obtained from a total of 12 molecular dynamics snapshots in two protonation states) cause notable, but still relatively minor, fluctuations in the computed energetic and structural properties.
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