Evidence for Stabilisation of Low Spin State of Cytochrome P450 due to Shortening of the Proximal Haem Bond


The cytochrome P450 superfamily of enzymes is ubiquitous, being responsible for the metabolism of a wide range of endogenous and xenobiotic compounds. However, the detailed mechanism of the catalytic cycle of these enzymes is still not fully understood. We describe results, obtained from first principles molecular simulations, which indicate that the low spin state of the Fe3+ ion, present in the haem moiety at the active site of a cytochrome P450 enzyme, may be stabilised by shortening of the proximal bond of the haem. Calculations indicate that a bond length of less than approx. 2.05 Angstroms between the haem Fe3+ ion and the cysteine S, which forms the proximal ligand, would result in the stabilisation of the low-spin state of the Fe3+, inhibiting the progress of the P450 catalytic cycle. Our investigation uses novel first principles modeling techniques which treat the entire system quantum-mechanically.

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Matthew Segall (mds21@phy.cam.ac.uk)
Last modified: Thu Jun 25 11:57:22 1998