Antioxidation activity of molecular hydrogen via protoheme catalysis in vivo: an insight from ab initio calculations

Abstract

Recently molecular hydrogen has been found to exhibit antioxidation activity through many clinical experiments, but the mechanism has not been fully understandable at atomic level. In this work, we perform systematic ab initio calculations of protohemehydrogen complexes to clarify the antioxidation mechanism of molecular hydrogen. We make molecular modeling of iron-protoporphyrin coordinated by imidazole, FeP(Im), and its hydrogen as well as dihydrogen complexes, together with reactive oxygen/nitrogen species (RONS). We carry out structural optimization and Mulliken charge analysis, revealing the two kinds of bonding characteristics between FeP(Im) and H 2 ; dihydrogen bonding in the end-on asymmetric configuration and Kubas bonding in the side-on symmetric configuration of H 2 molecule. The activation barriers for adsorption and dissociation of H 2 on and further desorption of H atom from FeP(Im) are found to be below 64 kcal/mol at most, which is remarkably lower than the H-H bond breaking energy of 107 kcal/mol in free H 2 molecule.We find that the hydrogen bond dissociation energies of FeP(Im)-H 2 and -H complexes are * Chol-Jun Yu; orcid.org/0000-0001-9523-4325

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

“…23 Taking account of the fact that heme is the active site of hemoglobin (Hb), the main component of blood cells, we recently carried out the systematic study of hydrogenprotoheme (Fe-protoporphyrin with an imidazole ligand: FePIm) complexes using density functional theory (DFT) calculations. 15 We suggested two types of bonding between H 2 and the Fe(II) of heme (dihydrogen and Kubas bonding), and revealed that H 2 can be dissociated with a relatively low activation barrier to form an FePIm-H complex, clarifying the key role of heme as an effective catalyst for antioxidant activity towards RONS by hydrogen gas. Some previous works also reported dihydrogen-metalloprotein complexes.…”

“…1a), and which has been widely used to study the reactions of small molecules with heme groups in DFT calculations. 15,34,35,44 Since FePIm is too large to be used for calculation of the rate constant with direct dynamics for variational transition state theory (DIR-DYVTST), the smaller models 1 and 2 were also considered. The chemical formulae of models 1 and 2 can be expressed as [Fe(C n H n+2 N 2 ) 2 NH 3 ], where n = 3 and 1, respectively.…”

“…The order of binding strength was NO > O 2 > CO > H > H 2 for the FePIm-based systems, while it was H > O 2 > NO > CO > H 2 for a PBE/DZP DFT supercell calculation. 15 b Experiment. 48 c B3LYP/ lacv3p**+ DFT cluster calculation.…”

“…Considering that cellular redox dysregulation occurs as a result of homeostasis depression between RONS and self-defense antioxidants, H 2 may react with RONS, typically the hydroxyl radical (cOH) and peroxynitrite (ONOO − ), in the presence of catalytic metal cations such as Fe 2+ and Cu + . 15,16 Although some enzymes, such as catalase and superoxide dismutase, may also alleviate RONS-induced cellular injury, 17 their clinical efficacy is little demonstrated because of their inability to permeate cell-membrane barriers. In addition, hydrogen has also been applied to treat cerebral ischemia by buffering the destructive effects of oxidative stress in the brain, proving its ability to cross the blood-brain barrier.…”

First-principles study of mercaptoundecanoic acid molecule adsorption and gas molecule penetration onto silver surface: an insight for corrosion protection

“…We checked that these computational settings for the PAO basis sets and the real spacing grid provided well converged results, as already proved in the previous works. 53–56…”