AB-INITIO CALCULATIONS ON IRON-PORPHYRIN MODEL SYSTEMS FOR INTERMEDIATES IN THE OXIDATIVE CYCLE OF CYTOCHROME P450S

Geometry optimizations for several spin states of the iron(III)-S-meth yl-porphyrin complex, the iron(III)-oxo-S-methyl-porphyrin complex and the respective anions were performed in order to examine models for i ntermediates in the oxidative cycle of cytochrome P450. The aim of thi s study was to obtain insights into the ground states of the intermedi ates of this catalytic cycle and to use the ab initio calculated geome tries and charge distributions to suggest better and more realistic pa rameters for forcefields which are generally used for modeling P450s. The results indicate that the ground states of both the iron(III)-S-me thyl-porphyrin complex and the iron(III)-oxo-S-methylporphyrin complex are sextet spin states (high spin). The ground states of the anions o f both complexes are probably quintet spin states. The fact that exper imentally a shift from low spin to high spin is observed upon binding of the substrate suggests that the ab initio calculations for the iron (III)S-methyl-porphyrin complex in vacuum give a correct representatio n of the (hydrophobic) substrate-bound state of the active site of P45 0. The ab initio geometries of the iron-porphyrin complexes are very s imilar to the experimentally observed geometries, except for the longe r iron-sulfur bond in ab initio calculations, which is probably caused by the omission of polarization functions on the sulfur atom during t he geometry optimization. The charge distribution in all ab initio cal culated complexes can be described by a series of concentric rings of alternating charge, thus allowing a relatively large positive charge o n the iron atom. The commonly used forcefields generally underestimate the charge differences between the iron atom and the different parts of the porphyrin moiety or ignore the charges completely. Although for cefield calculations can reproduce the experimental geometry of iron-p orphyrin moieties, extension of the forcefields with charges obtained from ab initio calculations should give a better description of the he me moiety in protein modeling and docking experiments.