Ab initio Quantum Mechanics/Molecular Mechanics Molecular Dynamics Simulation of CO in the Heme Distal Pocket of Myoglobin

Myoglobin has important biological functions in storing and transporting small diatomic molecules in human body. Two possible orientations of carbon monoxide (CO) in the heme distal pocket (named as B₁ and B₂ states) of myoglobin have been experimentally indicated. In this study, ab initio quantum mechanics/molecular mechanics (QM/MM) molecular dynamics simulation of CO in myoglobin was carried out to investigate the two possible B states. Our results demonstrate that the B₁ and B₂ states correspond to Fe…CO (with carbon atom closer to iron center of heme) and Fe…OC (with oxygen atom closer to Fe), by comparing with the experimental infrared spectrum. QM electrostatic polarization effect on CO brought from the protein and solvent environment is the main driving force, which anchors CO in two distinctive orientations and hinders its rotation. The calculated vibrational frequency shift between the state B₁ and B₂ is 13.1 cm^-1, which is in good agreement with experimental value of 11.5 cm^-1. This study also shows that the electric field produced by the solvent plays an important role in assisting protein functions by exerting directional electric field at the active site of the protein. From residue-based electric field decomposition, several residues were found to have most contributions to the total electric field at the CO center, including a few charged residues and three adjacent uncharged polar residues (namely, HIS64, ILE107, and PHE43). This study provides new physical insights on rational design of enzyme with higher electric field at the active site.