Skip to main content

Advertisement

SpringerLink
Log in

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

  • Original Paper
  • Published:
Journal of Molecular Modeling Aims and scope Submit manuscript

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 protoheme-hydrogen 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 2.78 eV at most, which is remarkably lower than the H–H bond breaking energy of 4.64 eV in free H\(_{2}\) molecule. We find that the hydrogen bond dissociation energies of FeP(Im)–H\(_{2}\) and –H complexes are lower than those of RONS–H complexes, indicating the decisive role of protoheme as an effective catalyst in RONS antioxidation by molecular hydrogen in vivo.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Code availability

Not applicable

Notes

  1. This code was originally developed by J. M. Knaup, and we modified the code to debug some minor errors and allow parallel running with a permission.

References

  1. Ohsawa I, Ishikawa M, Takahashi K, Watanabe M, Nishimaki K, Yamagata K, Katsura K, Katayama Y, Asoh S, Ohta S (2007) Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. Nat Med 13:688–694

    Article  CAS  PubMed  Google Scholar 

  2. LeBaron, TW, Kura, B, Kalocayova, B, Tribulová, N, Slezák, J (2019) A new approach for the prevention and treatment of cardiovascular disorders. molecular hydrogen significantly reduces the effects of oxidative stress. Molecules 24:2076

  3. Ohta S (2012) Molecular hydrogen is a novel antioxidant to efficiently reduce oxidative stress with potential for the improvement of mitochondrial diseases. Biochim Biophys Acta Gen Subj 1820:586–594

    Article  CAS  Google Scholar 

  4. LeBaron TW, Laher I, Kura B, Slezák J (2019) Hydrogen gas: from clinical medicine to an emerging ergogenic molecule for sports athletes. Can J Physiol Pharmacol 97:797–807

    Article  CAS  PubMed  Google Scholar 

  5. Slezák, J, Kura, B, Frimmel, K, Zálesák, M, Ravingerová, T, Viczencozová, C, Okruhlicová, L, Tribulová, N (2016) Preventive and therapeutic application of molecular hydrogen in situations with excessive production of free radicals. Physiol Res (Suppl 1) 65:S11-S28

  6. Huang CS, Kawamura T, Toyoda Y, Nakao A (2010) Recent advances in hydrogen research as a therapeutic medical gas. Free Radic Res 44:971–982

    Article  CAS  PubMed  Google Scholar 

  7. Barancik M, Kura B, LeBaron TW, Bolli R, Buday J, Slezak J (2020) Molecular and cellular mechanisms associated with effects of molecular hydrogen in cardiovascular and central nervous systems. Antioxidants 9:1281

    Article  CAS  PubMed Central  Google Scholar 

  8. Zhang Y, Tan S, Xu J, Wang T (2018) Hydrogen therapy in cardiovascular and metabolic diseases: from bench to bedside. Cell Physiol Biochem 47:1–10

    Article  PubMed  Google Scholar 

  9. Nakao A, Toyoda Y, Sharma P, Evans M, Guthrie N (2010) Effectiveness of hydrogen rich water on antioxidant status of subjects with potential metabolic syndrome - an open label pilot study. J Clin Biochem Nutr 46:140–149

    Article  PubMed  PubMed Central  Google Scholar 

  10. Ming Y, Ma Q, Han X, Li H (2020) Molecular hydrogen improves type 2 diabetes through inhibiting oxidative stress. Exp Ther Med 20:359–366

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Wang D, Wang L, Zhang Y, Zhao Y, Chen G (2018) Hydrogen gas inhibits lung cancer progression through targeting smc3. Biomed Pharmacother 104:788–797

    Article  CAS  PubMed  Google Scholar 

  12. Xia C, Liu W, Zeng D, Zhu L, Sun X, Sun X (2013) Effect of hydrogenrich water on oxidative stress, liver function, and viral load in patients with chronic hepatitis b. Clin Translation Sci 6:372–375

    Article  CAS  Google Scholar 

  13. Gao Y, Yang H, Chi J, Xu Q, Zhao L, Yang W, Liu W, Yang W (2017) Hydrogen gas attenuates myocardial ischemia reperfusion injury independent of postconditioning in rats by attenuating endoplasmic reticulum stress-induced autophagy. Cell Physiol Biochem 43:1503–1514

    Article  CAS  PubMed  Google Scholar 

  14. Takahashi M, Chen-Yoshikawa TF, Saito M, Tanaka S, Miyamoto E, Ohata K, Kondo T, Motoyama H, Hijiya K, Aoyama A, Date H (2017) Immersing lungs in hydrogen-rich saline attenuates lung ischaemia-reperfusion injury. Eur J Cardiothorac Surg 51:442–448

    PubMed  Google Scholar 

  15. Hu Q, Zhou Y, Wu S, Wu W, Deng Y, Shao A (2020) Molecular hydrogen: A potential radioprotective agent. Biomed Pharmacothe 130(110):589

    Google Scholar 

  16. Kura B, Bagchi AK, Singal PK, Barancik M, LeBaron TW, Valachova K, Šoltés L, Slezák J (2019) Molecular hydrogen: Potential in mitigating oxidative-stress-induced radiation injury. Can J Physiol Pharmacol 97:287–292

    Article  CAS  PubMed  Google Scholar 

  17. Benoit SL, Maier RJ, Sawers RG, Greening C (2020) Molecular hydrogen metabolism: a widespread trait of pathogenic bacteria and protists. Microbiol Mol Biol Rev 84(e00):092–19

    Google Scholar 

  18. Yao L, Chen H, Wu Q, Xie K (2019) Hydrogen-rich saline alleviates inflammation and apoptosis in myocardial I/R injury via PINK-mediated autophagy. Int J Mol Med 44:1048–1062

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Ichihara M, Sobue S, Ito M, Ito M, Hirayama M, Ohno K (2015) Beneficial biological effects and the underlying mechanisms of molecular hydrogen - comprehensive review of 321 original articles. Med Gas Res 5:1–21

    Article  Google Scholar 

  20. Ohta S (2014) Molecular hydrogen as a preventive and therapeutic medical gas: Initiation, development and potential of hydrogen medicine. Pharmacol Ther 144:1–11

    Article  CAS  PubMed  Google Scholar 

  21. Weidinger A, Kozlov AV (2015) Biological activities of reactive oxygen and nitrogen species: Oxidative stress versus signal transduction. Biomolecules 5:472–484

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Sobue S, Yamai K, Ito M, Ohno K, Ito M, Iwamoto T et al (2015) Simultaneous oral and inhalational intake of molecular hydrogen additively suppresses signalling pathways in rodents. Mol Cell Biochem 403:231–241

    Article  CAS  PubMed  Google Scholar 

  23. Yamamoto R, Homma K, Suzuki S, Sano M, Sasaki J (2019) Hydrogen gas distribution in organs after inhalation: Real-time monitoring of tissue hydrogen concentration in rat. Sci Rep 9:1255

    Article  PubMed  PubMed Central  Google Scholar 

  24. Yang Y, Zhu Y, Xi X (2018) Anti-inflammatory and antitumor action of hydrogen via reactive oxygen species. Oncol Lett 16:2771–2776

    PubMed  PubMed Central  Google Scholar 

  25. Ono H, Nishijima Y, Adachi N, Sakamoto M, Kudo Y, Kaneko K, Nakao A, Imaoka T (2012) A basic study on molecular hydrogen (H2) inhalation in acute cerebral ischemia patients for safety check with physiological parameters and measurement of blood H2 level. Med Gas Res 2:21

  26. Tamasawa A, Mochizuki K, Hariya N, Saito M, Ishida H, Doguchi S, Yanagiya S, Osonoi T (2015) Hydrogen gas production is associated with reduced interleukin-1β mRNA in peripheral blood after a single dose of acarbose in japanese type 2 diabetic patients. Eur J Pharmacol 762:96–101

  27. Qian L, Shen J, Sun X (2015) Hydrogen molecular biology and medicine. Springer

    Google Scholar 

  28. Hanaoka T, Kamimura N, Yokota T, Takai S, Ohta S (2011) Molecular hydrogen protects chondrocytes from oxidative stress and indirectly alters gene expressions through reducing peroxynitrite derived from nitric oxide. Med Gas Res 1:18

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Kiyoi T, Liu S, Takemasa E, Nakaoka H, Hato N, Mogi M (2020) Constitutive hydrogen inhalation prevents vascular remodeling via reduction of oxidative stress. PLoS ONE 15(e0227):582

    Google Scholar 

  30. Ge YS, Zhang QZ, Li H, Bai G, Jiao ZH, Wang HB (2019) Hydrogen-rich saline protects against hepatic injury induced by ischemia-reperfusion and laparoscopic hepatectomy in swine. Hepatobiliary Pancreat Dis Int 18:48–61

    Article  PubMed  Google Scholar 

  31. Itoh T, Fujita Y, Masuda A, Ohno K, Ichihara M, Kojima T, Nozawa Y, Ito M (2009) Molecular hydrogen suppresses Fc epsilon RI-mediated signal transduction and prevents degranulation of mast cells. Biochem Biophys Res Commun 389:651–656

    Article  CAS  PubMed  Google Scholar 

  32. Itoh T, Hamada N, Terazawa R, Ito M, Ohno K, Ichihara M, Nozawa Y, Ito M (2011) Molecular hydrogen inhibits lipopolysaccharide/interferon γ-induced nitric oxide production through modulation of signal transduction in macrophages. Biochem Biophys Res Commun 411:143–149

  33. Iuchi K, Imoto A, Kamimura N, Nishimaki K, Ichimiya H, Yokota T, Ohta S (2016) Molecular hydrogen regulates gene expression by modifying the free radical chain reaction-dependent generation of oxidized phospholipid mediators. Sci Rep 6(18):971

    Google Scholar 

  34. Varga V, Németh J, Oláh O, Tóth-Szüki V, Kovács V, Remzsö G, Domoki F (2018) Molecular hydrogen alleviates asphyxia-induced neuronal cyclooxygenase-2 expression in newborn pigs. Acta Pharmacol Sin 39:1273–1283

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Chen CH, Manaenko A, Zhan Y, Liu WW, Ostrowki RP, Tang J, Zhang JH (2010) Hydrogen gas reduced acute hyperglycemia-enhanced hemorrhagic transformation in a focal ischemia rat model. Neuroscience 169:402–414

    Article  CAS  PubMed  Google Scholar 

  36. Yang Y, Estrada EY, Thompson JF, Liu W, Rosenberg G (2007) Matrix metalloproteinase-mediated disruption of tight junction proteins in cerebral vessels is reversed by synthetic matrix metalloproteinase inhibitor in focal ischemia in rat. J Cereb Blood Flow Metab 27:697–709

    Article  CAS  PubMed  Google Scholar 

  37. Shi P, Sun W, Shi P (2012) A hypothesis on chemical mechanism of the effect of hydrogen. Med Gas Res 2:17

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Kubas GJ, Ryan RR, Swanson BI, Vergamini PJ, Wasserman HJ (1984) Characterization of the first examples of isolable molecular hydrogen complexes, M(CO)3(PR3)2(H2) (M = Mo, W, R = Cy, i-Pr), evidence for a side-on bonded H2 ligand. J Am Chem Soc 106:451–452

  39. Jean Y, Eisenstein O, Volatron F, Maouche B, Sefta F (1986) Interaction between d6 ML5 metal fragments and hydrogen: η2-H2 vs. dihydride structure. J Am Chem Soc 108:6587–6592

  40. Soler JM, Artacho E, Gale JD, García A, Junquera J, Ordejón P, Sánchez-Portal D (2002) The SIESTA method for ab initio order-N materials simulation. J Phys: Condens Matter 14:2745

    CAS  Google Scholar 

  41. Artacho E, Anglada E, Diéguez O, Gale JD, García A, Junquera J, Martin RM, Ordejón P, Pruneda JM, Sánchez-Portal D, Soler JM (2008) The SIESTA method; developments and applicability. J Phys: Condens Matter 20(064):208

    Google Scholar 

  42. Troullier N, Martins JL (1991) Efficient pseudopotentials for plane-wave calculations. Phys Rev B 43:1993–2006

    Article  CAS  Google Scholar 

  43. Hamann DR (1989) Generalized norm-conserving pseudopotentials. Phys Rev B 40:2980–2987

    Article  CAS  Google Scholar 

  44. Perdew JP, Burke K, Ernzerhof M (1996) Generalized gradient approximation made simple. Phys Rev Lett 77:3865

    Article  CAS  PubMed  Google Scholar 

  45. Grimme S (2006) Semiempirical GGA-type density functional constructed with a long-range dispersion correction. J Comput Chem 27:1787–1799

    Article  CAS  PubMed  Google Scholar 

  46. Arcon JP, Rosi P, Petruk AA, Marti MA, Estrin DA (2015) Molecular mechanism of myoglobin autoxidation: Insights from computer simulations. J Phys Chem B 119:1802–1813

    Article  CAS  PubMed  Google Scholar 

  47. Degtyarenko I, Biarnés X, Nieminen RM, Rovira C (2008) Density-functional molecular dynamics studies of biologically relevant iron and cobalt complexes with macrocyclic ligands. Coord Chem Rev 252:1497–1513

    Article  CAS  Google Scholar 

  48. Degtyarenko I, Nieminen RM, Rovira C (2006) Structure and dynamics of dioxygen bound to cobalt and iron heme. Biophys J 91:2024–2034

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Henkelman G, Uberuaga BP, Jónsson H (2000) A climbing image nudged elastic band method for finding saddle points and minimum energy paths. J Chem Phys 113:9901–9904

    Article  CAS  Google Scholar 

  50. Yu CJ, Kye YH, Jong UG, Ri KC, Choe SH, Kim JS, Ko SG, Ryu GI, Kim B (2020) Interface engineering in hybrid iodide CH3NH3PbI3 perovskites using Lewis base and graphene toward high-performance solar cells. ACS Appl Mater Interfaces 12:1858–1866

  51. Kim, YS, Ri, CH, Ko, UH, Kye, YH, Jong, UG, Yu, CJ (2021) Interfacial enhancement of photovoltaic performance in MAPbI3/CsPbI3 superlattice. ACS Appl Mater Interfaces 13:14,679-14,687

  52. Boys SF, Bernardi F (1970) The calculation of small molecular interactions by the differences of separate total energies. some procedures with reduced errors. Mol Phys 19:553–566

    Article  CAS  Google Scholar 

  53. van Duijneveldt FB, Van Duijneveldt-Van De R, GCM J, Van Lenthe JH (1994) State of the art in counterpoise theory. Chem Rev 94:1873–1885

    Article  Google Scholar 

  54. Momma K, Izumi F (2011) VESTA 3 for three-dimensional visualization of crystal, volumetric and morphology data. J Appl Crystallogr 44:1272–1276

    Article  CAS  Google Scholar 

  55. Anouar EH, Raweh S, Bayach I, Taha M, Baharudin MS, Meo FD, Hasan MH, Adam A, Ismail NH, Weber JFF, Trouillas P (2013) Antioxidant properties of phenolic Schiff bases: Structure-activity relationship and mechanism of action. J Comput Aided Mol Des 27:951–964

    Article  CAS  Google Scholar 

  56. Parr RG, Yang W (1989) Density functional theory of atoms and molecules. Oxford University Press

  57. Tsuda M, Dino WA, Nakanishi H, Kasai H (2005) Orientation dependence of O2 dissociation from heme-O2 adduct. Chem Phys Lett 402:71–74

  58. Tsuda M, Dy ES, Kasai H (2006) Side-on O2 interaction with heme-based nanomaterials. Eur Phys J D 38:139–141

  59. Brucker, EA, Olson, JS, Phillips, GN, Dou, Y, IkedaSaito, M (1996) High resolution crystal structures of the deoxy, oxy, and aquomet forms of cobalt myoglobin. J Biol Chem 271:25,419-25,422

  60. Vojtechovsky J, Chu K, Berendzen J, Sweet RM, Schlichting I (1999) Crystal structures of myoglobin-ligand complexes at near-atomic resolution. Biophys J 77:2153–2174

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Kubas GJ (1988) Molecular hydrogen complexes: Coordination of a sigma bond to transition metal. Acc Chem Res 21:120–128

    Article  Google Scholar 

  62. Vladimir, IB (2008) Dihydrogen bond: Principles, Experiments, and Applications. John Willey Sons. Inc

  63. Guo L, Li SY, Zhang X, Zhang RJ, Guo J (2013) Hydrogen adsorption and dissociation on small AlnAu clusters: An electronic structure density functional study. Eur Phys J D 67:137

  64. Meisner, J, Kästner, J (2016) Reaction rates and kinetic isotope effects of Hn + OH → H2O + H. J Chem Phys 144

  65. Nguyen TL, Stanton JF, Barker JR (2011) Ab initio reaction rate constants computed using semiclassical transition-state theory: HO + H2 → H2O + H and isotopologues. J Phys Chem A 115:5118–5126

Download references

Acknowledgements

Computations have been done on the HP Blade System C7000 (HP BL460c) that is managed by Faculty of Materials Science, Kim Il Sung University.

Funding

This work was supported by the State Commission of Science and Technology, DPR Korea.

Author information

Authors and Affiliations

  1. Faculty of Chemistry, Kim Il Sung University, Ryongnam-Dong, Taesong District, Pyongyang, PO Box 76, Democratic People’s Republic of Korea

    Song-Ae Kim & Yu-Chol Jong

  2. Faculty of Life Science, Kim Il Sung University, Ryongnam-Dong, Taesong District, Pyongyang, PO Box 76, Democratic People’s Republic of Korea

    Myong-Su Kang

  3. Faculty of Materials Science, Kim Il Sung University, Ryongnam-Dong, Taesong District, Pyongyang, PO Box 76, Democratic People’s Republic of Korea

    Chol-Jun Yu

Authors
  1. Song-Ae Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yu-Chol Jong
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Myong-Su Kang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chol-Jun Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

The original project was developed by Song-Ae Kim and Yu-Chol Jong. Calculations, data collection and analysis were performed by Chol-Jun Yu. The first draft of the manuscript was written by Yu-Chol Jong and all authors contributed to useful discussions. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Chol-Jun Yu.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file 1 (pdf 1875 KB)

Rights and permissions

Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kim, SA., Jong, YC., Kang, MS. et al. Antioxidation activity of molecular hydrogen via protoheme catalysis in vivo: an insight from ab initio calculations. J Mol Model 28, 287 (2022). https://doi.org/10.1007/s00894-022-05264-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s00894-022-05264-y

Keywords

Search

Navigation