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.