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New AMBER force field parameters of heme iron for cytochrome P450s determined by quantum chemical calculations of simplified models



The heme protein, cytochrome P450, is an oxidoreductase that plays an important role in drug metabolism. To model P450s using molecular mechanics methods and classical molecular dynamics simulations, force field parameters and atomic charges are required. Because these parameters are generally obtained by quantum chemical methods, an appropriate simplified model for the iron–porphyrin system was needed. In this study, two models with a five-coordinated Fe(III) mimicking the sextet spin state of P450s are proposed, which are optimized by semiempirical and ab initio unrestricted Hartree–Fock methods. The results produced using the simpler of the two models were similar to those of the more complex model; therefore, the more simplified model of P450 can be used without a loss of accuracy. Furthermore, several quantum chemical calculations were carried out on the simpler model to investigate which method was most suitable for iron–porphyrin systems. The results calculated by hybrid density functional theory (DFT), with the MIDI basis set for iron, reproduced the three-dimensional structures determined by X-ray diffraction and extended X-ray absorption fine-structure experiments. From these results, atomic charges and force-field parameters for molecular mechanics and molecular dynamics calculations were obtained. © 2005 Wiley Periodicals, Inc. J Comput Chem 26: 818–826, 2005