First-principles study of molecular hydrogen binding to heme in competition with O2, NO and CO

Abstract

Molecular hydrogen shows antioxidant activity and distinct efficacy towards vascular diseases, but the understanding of this is not yet satisfactory at the atomic level. In this work, we study the binding properties of H₂ to the heme group in relation with other diatomic molecules (DMs), including O₂, NO and CO, and their displacement reactions, using first-principles calculations. We carry out molecular modeling of the heme group, using iron-porphyrin with the imidazole ligand, i.e., FePIm, and smaller models of Fe(C_nH_n+2N₂)₂NH₃ with n = 3 and 1, and of molecular complexes of heme-DM and -H. Through analysis of optimized geometries and energetics, it is found that the order of binding strength of DMs or H to the Fe of heme is NO > O₂ > CO > H > H₂ for FePIm-based systems, while it is H > O₂ > NO > CO > H₂ for model-based systems. We calculate the activation energies for displacement reactions of H₂ and H by other DMs, revealing that the H₂ displacements occur spontaneously while the H displacements require a large amount of energy. Finally, our calculations corroborate that the rate constants increase with increasing temperature according to the Arrhenius relation.

Fig. 1. Molecular structures of (a) Fe-porphyrin with the imidazole ligand (FePIm), (b) model1, Fe(C₃H₅N₂)₂NH₃, and (c) model2, Fe(CH₃N₂)₂NH₃.

Fig. 2. Optimized geometries of heme–DM and –H compounds, where heme is modeled by FePIm, model1 and model2, and the DMs are H₂, O₂, NO and CO. The highest occupied molecular orbitals (HOMOs) and the lowest unoccupied molecular orbitals (LUMOs) are presented with the MO levels in eV units. The DFT method with B3LYP/6-311G and LANL2DZ_ECP was utilized.

Fig. 3. Energy profiles (bottom panels) for displacement reactions of a H₂ molecule (a–c) or H atom (d–f) bound to heme modeled using FePIm, model1 and model2. The optimized geometries (top panels) of molecular complexes composed of FePIm, H₂ or H, and a DM, namely O₂ (a and d), NO (b and e), and CO (c and f) are shown, corresponding to the initial state (IS), transition state (TS) and final state (FS).

Fig. 4. Rate constants (k; black colour) and equilibrium constants (K; blue colour) of H₂ displacement reactions with O₂, NO and CO on model2 in the (a) forward and (b) backward directions as functions of temperature. Red-coloured solid lines indicate the regressions into the Arrhenius equation.

Fig. 5. Rate constants (k; black colour) and equilibrium constants (K; blue colour) of H displacement reactions with O₂, NO and CO on model2 in the (a) forward and (b) backward directions as functions of temperature. Red-coloured solid lines indicate the regressions into the Arrhenius equation.