High-level Density functional theory (DFT) has been employed to investigate the impact of substitutions onto the imidazole (IM) ring, mimicking the effect of the substituted axial histidine on the bonding of the CO and NO ligands with Ferrous-Heme. It has been predicted that the CO and NO bonding to Heme is sensitive to the nature of substitution groups. Also, it has been predicted that in contrast to electron-donating substitutions on the IM ring, the electron-withdrawing groups have mainly a stabilization effect (though slightly) on the bonding of CO and NO to Heme.
