Application of molecular dynamics and free energy perturbation methods to metalloporphyrin‐ligand systems ii: Co and dioxygen binding to myoglobin

Abstract

The protein contribution to the relative binding affinity of the ligands CO and O2 toward myoglobin (Mb) has been simulated using free energy perturbation calculations. The tautomers of the His E7 residue are different for the oxymyoglobin (MbO2) and carboxymyoglobin (MbCO) systems. This was modeled by performing two‐step calculations that mutate the ligand and mutate the His E7 tautomers in separate steps. Differences in hydrogen bonding to the O2 and CO ligands were incorporated into the model. The O2 complex was calculated to be 2–3 kcal/mol more stable than the corresponding CO complex when compared to the same difference in an isolated heme control. This value agrees well with the experimental value of 2.0 kcal/mol. In qualitative agreement with experiments, the Fe‐C‐O bond is found to be bent (θ = 159.8°) with a small tilt (ϕ = 6.2°). The contributions made by each of the 29 residues — within the 9.0‐Å radius of the iron atom — to the free energy difference are separated into van der Waals and electrostatic contributions; the latter contributions are dominant. Aside from the proximal histidine and the heme group, the residues having the largest difference in free energy in mutating MbO2 → MbCO are His E7, Phe CD1, Phe CD4, Val E11, and Thr E10.

The distal residue-CO interaction in carbonmonoxy myoglobins: a molecular dynamics study of two distal histidine tautomers

“…Although the interaction of Fe bound CO with the protein is expected to be weaker because of a less favorable geometry, the Fe-C-O unit itself is more polarizable; it is therefore plausible that the presence, or otherwise, of the distal side chain can account for the observed shifts in the vco frequency of the A states. Lopez and Kollman (1993) have recently found a 0.74 kcal/mol free energy difference between the two distal histidine tautomers of MbCO, suggesting, as found here, that there are significant differences in the distal-CO interaction between the two tautomers. Their calculation was performed, however, in vacuo, and their result is subject to a large error (±0.78 kcal/mol).…”

“…Only recently has a detailed force field been developed for the haem prosthetic group of the globin proteins (Kuczera et al, 1990), and a number of calculations have been published concerning the photodissociation dynamics of a CO ligand (considering the 64N8H tautomer and the 64His+ distal residues) (Straub and Karplus, 1991;Petrich et al, 1991), the vacuum dynamics of 64N,H MbCO (Kuczera et al, 1990;Henry, 1993), and the diffusion of ligands through the protein (Elber and Karplus, 1990). The free energy difference between the two distal histidine tautomers of neutral pH MbCO has also been recently considered (Lopez and Kollman, 1993). In this study, a total of four 90 ps trajectories have been calculated, differing in primary structure only in the protonation site of the distal histidine side chain, which is shown in Fig.…”

Myoglobin and CO: structure, energetics, and disorder

“…Accurate molecular mechanics potentials can estimate changes in the global protein energy on CO binding [40,41]. Improved understanding of the heme-CO energetics and increasingly precise structural information should provide the guidance needed for a quantitative theoretical evaluation of steric inhibition of CO binding in heme proteins.…”

Will the real FeCO please stand up?

“…1), since the Fe ) O distance , is much greater than the C-O distance. In a later molecular mechanics calculation, Lopez and Kollman [34] optimized the MbCO geometry, and calculated a 67 tilt and an Fe-C-O angle of 174 or 1607, depending on the assumed tautomer of the distal histidine. Both these calculations used FeCO force constants transferred from the Cr(CO) 6 molecule, but Li and Spiro [18] found that a substantially higher FeCO bending constant was required to fit the ob- Fig.…”