AN AB-INITIO APPROACH TO THE UNDERSTANDING OF CYTOCHROME-P450 LIGAND INTERACTIONS

1. We describe the application of novel ab initio quantum mechanical m ethods to the study of ligand interactions with cytochrome P450(cam) ( CYP101). 2. We find that our techniques accurately describe the transi tion from a low-spin state to a high-spin state of the haem Fe3+ on bi nding of a substrate. Furthermore, our methods correctly predict that a large fraction of low-spin character is retained on binding of an in hibitor. 3. We demonstrate the use of 'computational experiments' to e lucidate key features of the mechanism of interaction. This leads us t o identify a new mechanism for the suppression of the low-to high-spin transition on binding of an inhibitor, namely the shortening of the b ond between the Fe atom and the coordinated S atom of the cysteine axi al ligand.