Hydrogen Bonding in Human P450-Substrate Interactions: A Major Contribution to Binding Affinity

David F.V Lewis

doi:10.1100/tsw.2004.210

Abstract

The importance of hydrogen bonding, a relatively strong intermolecular force of attraction between molecules in biological systems, is discussed in the respect of P450 substrate affinity towards one or more of the human P450 enzymes that are generally associated with drug and other xenobiotic metabolism. It is shown that calculation of hydrogen bond distances and energies based on simple empirical relationships provide values that agree closely with experimental findings. It is thus possible to estimate the hydrogen bond contribution to P450 enzyme-substrate binding affinity based on modelled interactions and by use of these relatively simple formulae, particularly when employed in conjunction with substrate-lipophilicity relationships.

Highlights

The cytochromes P450 (CYP) constitute a superfamily of heme-thiolate enzymes that have been reported in all biological kingdoms and in most species
It has been proved possible to derive homology models of many P450 enzymes from appropriate crystallographic templates and, for human P450s, the recently reported rabbit CYP2C5 structure appears to be of particular benefit
It can be assumed that this is one of the major contributions to the overall binding energy between substrate and enzyme in P450-substrate interactions. Evidence for this comes from the location of potential hydrogen bond acceptors and donors in P450 crystal structures

Summary

INTRODUCTION

The cytochromes P450 (CYP) constitute a superfamily of heme-thiolate enzymes that have been reported in all biological kingdoms and in most species. In many of the P450 structures investigated far, including both models and crystallographic coordinates, the ubiquitous importance of hydrogen bonding between enzyme and substrate has been emphasized. It can be assumed that this is one of the major contributions to the overall binding energy between substrate and enzyme in P450-substrate interactions. Evidence for this comes from the location of potential hydrogen bond acceptors and donors in P450 crystal structures. In the substrate-bound CYP101 structure, the substrate camphor is positioned directly above the heme moiety for 5-exo hydroxylation by apparently forming a hydrogen bond with the tyrosine-96 residue. A simple calculation based on compound lipophilicity and average hydrogen bond energy gives a good estimate of the camphor substrate binding energy of CYP101, which is in satisfactory agreement with the experimentally determined value[1]

Estimation of Hydrogen Bond Lengths and Energies

Hydrogen Bond Type

CONCLUSIONS

Hexamethyl benzene