Heme Protein Oxygen Affinity Regulation Exerted by Proximal Effects

Heme proteins are found in all living organisms and are capable of performing a wide variety of
tasks, requiring in many cases the binding of diatomic ligands, namely, O2, CO, and/or NO. Therefore,
subtle regulation of these diatomic ligands' affinity is one of the key issues for determining a heme protein's
function. This regulation is achieved through direct H-bond interactions between the bound ligand and the
protein, and by subtle tuning of the intrinsic heme group reactivity. In this work, we present an investigation
of the proximal regulation of oxygen affinity in Fe(II) histidine coordinated heme proteins by means of
computer simulation. Density functional theory calculations on heme model systems are used to analyze
three proximal effects:  charge donation, rotational position, and distance to the heme porphyrin plane of
the proximal histidine. In addition, hybrid quantum-classical (QM-MM) calculations were performed in two
representative proteins:  myoglobin and leghemoglobin. Our results show that all three effects are capable
of tuning the Fe−O2 bond strength in a cooperative way, consistently with the experimental data on oxygen
affinity. The proximal effects described herein could operate in a large variety of O2-binding heme proteinsin combination with distal effectsand are essential to understand the factors determining a heme protein's
O2 affinity.