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, O-2, 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-O-2 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 O-2-binding heme proteins-in combination with distal effects-and are essential to understand the factors determining a heme protein's O-2 affinity.