This chapter described the application of ab initio modeling to the cytochrome P450 superfamily of enzymes. These enzymes are of great importance in pharmacology and toxicology and are the subject of current research in these fields. The experimental background and important physical properties of these enzymes were discussed in Section . An important signature of the reaction was identified, namely the change of the haem ion from a LS to HS state on binding of a substrate. An approach to the simulation of the interaction between ligand molecules and the active site of these enzymes was discussed in Section . The results of these simulations were presented in Section . These results indicated that the methods applied could accurately reproduce the spin state of the ion, clearly differentiating between the LS and HS cases. Furthermore, an unexpected mechanism for the stabilisation of the LS state of the ion was identified: the shortening of the distal bond between the haem iron and cysteine sulphur. This change in bond length was found to be caused by the presence of an -coordinated water molecule in the substrate analogue-bound systems.
One goal of this study was to develop techniques for predicting the activity of a molecule with a P450 enzyme. The results in this chapter represent a first step towards this goal. They indicate that the factors determining the spin state of the ion, which in turn determines the progress of the reaction, include the distortion of the haem, the length of the Fe-S bond as well as the presence of a sixth axial ligand to the ion. Thus, we can conclude that any approach to predicting the outcome of an interaction between a ligand molecule and a P450 must allow the haem to relax into its equilibrium geometry. The simulation of a larger fragment of the P450 molecule will probably be necessary in order to perform such a relaxation in order to ensure that the forces acting on the active site are accurately reproduced. The use of an ab initio technique which permits the efficient calculation of forces will therefore be essential in order to perform this ionic minimisation in a reasonable time.
An important conclusion of this study is that the ligand-P450 interactions can be modelled by considering only a small fragment of the P450 molecule, comprising the haem moiety and haem-ligated cysteine residue. These calculations open the possibility of many other avenues of enquiry including first principles calculations of redox potentials and the calculation of the structures and energies of the oxygen-bound intermediary states which are not directly accessible to conventional experiments (see Figure ). These calculations will require the modeling of larger systems, including additional residues in the active site. However, these calculations should be tractable given the computing power that is now available from high-performance parallel computers.