On the role of the axial ligand in heme proteins: a theoretical study

We present a systematic investigation of how the axial ligand in heme proteins influences the geometry, electronic structure, and spin states of the active site, and the energies of the reaction cycles. Using the density functional B3LYP method and medium-sized basis sets, we have compared models with His, His+Asp, Cys, Tyr, and Tyr+Arg as found in myoglobin and hemoglobin, peroxidases, cytochrome P450, and heme catalases, respectively. We have studied 12 reactants and intermediates of the reaction cycles of these enzymes, including complexes with H2O, OH−, O2–, CH3OH, O2, H2O2, and HO2– in various formal oxidation states of the iron ion (II to V). The results show that His gives ~0.6 V higher reduction potentials than the other ligands. In particular, it is harder to reduce and protonate the O2 complex with His than with the other ligands, in accordance with the O2 carrier function of globins and the oxidative chemistry of the other proteins. For most properties, the trend Cys<Tyr<Tyr+Arg<His+Asp<His is found, reflecting the donor capacity of the various ligands. Thus, it is easier to reduce compound I with a His+Asp ligand than with a Cys ligand, in accordance with the one-electron chemistry of peroxidases and the hydroxylation reactions of cytochromes P450. However, the Tyr complexes have an unusually low affinity for all neutral ligands, giving them a slightly enhanced driving force in the oxidation of H2O2 by compound I.