First Principles Investigation of Singly-reduced Cytochrome P450

Abstract

1. We describe the application of novel ab initio quantum mechanical methods to the states in the catalytic cycle of cytochrome P450 following the first reduction step.
2. We find a good correlation between the calculated energy of reduction and the experimentally determined redox potential for a range of substrate- and substrate analogue-bound systems.
3. On reduction of the haem system the ground state of the Fe is found to remain Fe3+. On binding of a CO molecule the Fe is found to adopt a low-spin Fe2+ state, in agreement with experiment. However, on binding of an O2 molecule our calculations indicate that the system adopts a ferric superoxide ground state, in which the Fe is in a low-spin Fe3+ state.