Steric contributions to CO binding in heme proteins: a density functional analysis of <font>FeCO</font> vibrations and deformability

Non-local Density Functional Theory (DFT) is applied to the calculation of geometry and vibrational frequencies of FeII (porphine)(imidazole)(CO), a model for CO adducts of heme proteins. Bond distances and angles are in agreement with crystallographic data, and frequencies are correctly calculated for C–O and Fe–C stretching and for Fe–C - O bending. This last mode is actually the out-of-phase combination of Fe–C–O bending and Fe–C tilting coordinates, which are heavily mixed because of a large bend–tilt interaction force constant. The in-phase combination is predicted at a very low frequency, 73 cm-1, and to have a low infrared intensity; attempts to detect it in far-IR spectra via 13 C 18 O isotope sensitivity have been unsuccessful. The stretch–bend interaction lowers the energy required for FeCO distortion. A soft potential may account for the wide range of crystallographically determined Fe–C–O displacements and orientations in myoglobin ( Mb ). The minimum energy path for displacement of the O atom from the heme normal was calculated by relaxing the structure while constraining only the O atom displacement from the heme normal. Energies of 0.2 to 3.5 kcal mol-1 are required for the range of reported displacement, 0.3–1.3 Å. However, vibrational spectroscopy limits the allowable displacement to the low end of this range. The O atom displacement is computed via DFT to be 0.6 Å for a 7 ° angle of the C–O stretching IR dipole relative to the heme normal, the maximum value compatible with IR polarization measurements on MbCO . FeCO distortion is predicted to diminish both ν CO and ν FeC , thereby producing deviations from the well-established backbonding correlation; the scatter of the data permits a maximum displacement of 0.5 Å. This displacement would cost about 1.6 kcal mol-1 of steric energy. A small distortion energy is consistent with the CO affinity changes produced by mutations of the distal histidine residue in Mb . Taking the leucine mutant as reference, we estimate the 1.6 kcal mol-1 affinity loss in the wild-type protein to be the resultant of a 0.0–1.6 kcal steric inhibition, a 0.5 kcal mol-1 attraction of the distal histidine sidechain for the bound CO [weak H -bond], and a 0.5–2.1 kcal mol-1 attraction of the same side-chain for a water molecule in the deoxy protein. The observed 2.3 kcal mol-1 O 2 affinity increase in the wild-type protein relative to the leucine mutant then implies a 2.8–4.4 kcal mol-1 attraction of the histidine sidechain for bound O 2, consistent with a substantial H -bond interaction with the distal histidine. Thus steric inhibition can account for only a minor fraction of the discrimination factor against CO and in favor of O 2 which is produced by the heme–myoglobin interaction.

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