QM/MM assessment of the proton and electron affinities of ligated heme iron centers in various enzyme families

Anikó Lábas, Balázs Krámos, Tibor Szilvási, and Julianna Oláh

Heme, an iron porphyrin, is one of the most important prosthetic groups in metalloproteins. It is the active agent of various enzyme families, e.g. if cytochrome P450s, peroxidases and globins. These proteins show striking diversity in their mode of action, and are involved in many biological processes, like drug metabolism or hormone synthesis. A remarkable feature of cytochrome P450 enzymes is their ability to oxidize inert carbon-hydrogen bonds, which keeps on inspiring the design of novel catalysts. The generally accepted mechanism of cytochrome P450s is called “rebound mechanism”: compound I abstracts a hydrogen from the substrate to form the hydroxo complex and a substrate radical, which are rapidly recombined to generate the hydroxylated product.[1] The ability of the FeIV-oxo complex to abstract a hydrogen is facilitated by the electron push effect of the proximal ligand and is related to the bond energy of the forming O-H bond (D(O-H)) of the hydroxo complex. This bond energy can be approximated by an empirical form,[2] containing the pKa of hydroxo complex and the one-electron reduction potential of compound I:D(O-H) = 23.06 • E0compound I + 1.37 • pKa,hydroxo complex + constant

The goal of this computational study is to compare the relationship between the proton and electron affinities of the heme centres of various enzyme families (CYPs, APOs, HRP, LiP) and to examine the electron donating effect of the different proximal ligands. For this, molecular dynamics simulations were carried out in the hydroxo complex state, and QM/MM geometry optimizations of a large number of protein conformations were carried out in order to collect statistically significant data that can be used to estimate the pKa and redox potential values of the various enzymes.

Acknowledgement: This work was supported by Gedeon Richter Plc. and OTKA Grant No 108721.

[1] John T. Groves, Nat. Chem.2014, 6, 89–91.
[2] James M. Mayer, Acc. Chem. Res. 1998, 31, 441-450.