An ab initio approach to the understanding of cytochrome P450-ligand interactions

Abstract

1. We describe the application of novel ab initio quantum mechanical methods to the study of ligand interactions with cytochrome P450_cam (CYP101). 2. We find that our techniques accurately describe the transition from a low-spin state to a high-spin state of the haem Fe⁺³ on binding of a substrate. Furthermore,our methods correctly predict that a large fraction of low-spin character is retained on binding of an inhibitor. 3. We demonstrate the use of ' computationalexperiments' to elucidate key features of the mechanism of interaction. This leads us to identify a new mechanism for the suppression of the low- to high-spin transition on binding of an inhibitor, namely the shortening of the bond between the Fe atom and the coordinated S atom of the cysteine axial ligand.