Water Complexes of Cytochrome P450: Insights from Energy Decomposition Analysis

Nandun Thellamurege,Hajime Hirao

doi:10.3390/molecules18066782

Abstract

Water is a small molecule that nevertheless perturbs, sometimes significantly, the electronic properties of an enzyme’s active site. In this study, interactions of a water molecule with the ferric heme and the compound I (Cpd I) intermediate of cytochrome P450 are studied. Energy decomposition analysis (EDA) schemes are used to investigate the physical origins of these interactions. Localized molecular orbital EDA (LMOEDA) implemented in the quantum chemistry software GAMESS and the EDA method implemented in the ADF quantum chemistry program are used. EDA reveals that the electrostatic and polarization effects act as the major driving force in both of these interactions. The hydrogen bonding in the Cpd I•••H2O complex is similar to that in the water dimer; however, the relative importance of the electrostatic effect is somewhat larger in the water dimer.

Highlights

The ubiquitous heme-containing monooxygenase, cytochrome P450 (P450), has been extensively studied both experimentally and computationally, because of the important role it plays in oxygenating organic compounds [1,2,3,4]
The distal ligand is an oxo group that is transferred to the substrate during the reaction, and thereafter, the oxygenated product is released from the active site to restore P450 to the resting state
We focus on the interaction of H2O with the ferric heme unit in 1 and Compound I (Cpd I) in 2

Summary

Introduction

The ubiquitous heme-containing monooxygenase, cytochrome P450 (P450), has been extensively studied both experimentally and computationally, because of the important role it plays in oxygenating organic compounds [1,2,3,4]. Compound I (Cpd I) is an oxoiron(IV) porphyrin π-cation radical (2 in Figure 1), and is believed to be responsible for the monooxygenase activity of P450s [5,6] In this case, the distal ligand is an oxo group that is transferred to the substrate during the reaction, and thereafter, the oxygenated product is released from the active site to restore P450 to the resting state. It has been noted that a H2O molecule interacting with the oxo ligand of Cpd I lowers the activation barrier for the H-abstraction step, and that this interaction is mainly of electrostatic origin [10,11] This interaction has been calculated using a QM/MM method [12]

Methods

Results

Conclusion