The cytochromes P450 (P450s) are a superfamily of enzymes which are found in all forms of living organism. They are responsible for the metabolism of many endogenous compounds, participate in the activation/deactivation of many carcinogens and detoxify many xenobiotics. In particular, in humans they metabolise many drugs and hence are of great interest to pharmacologists and toxicologists.
This chapter describes the application of ab initio methods to
the study of P450s. There are two principle goals for this
investigation. Firstly, ab initio simulations may aid in the
understanding of the detailed mechanisms of the interaction of ligand
molecules with the active site of an enzyme. The ultimate goal is the
development of techniques for the prediction of the outcome of such an
interaction. The results presented in this chapter represent the first
step along the route to this goal. They demonstrate that the methods
applied accurately reproduce experimental observations of the activity
of the enzyme and the use of `computational experiments' allows key
features of the reaction mechanism to be identified. The cytochrome
P450 system offers an ideal first target for ab initio methods
as the reaction has a clear signature, described in Section
, which may be identified in the results of
simulations.
Section gives a brief history of the
experimental investigation of the P450 family of enzymes, a summary of
the catalytic cycle of P450s as currently understood and some
important experimental results and properties of the enzymes. A more
complete account of the properties of P450s may be found in
the book edited by Omura et al. [76] or that by Lewis
[77]. The approach used for the study of the interactions
between ligand molecules and the active site of a P450 is described in
Section and the results obtained from the investigation
are given in Section . Finally, a summary of this
chapter is given in Section .