Skip to main content
SpringerLink
Log in

Conformations of Oxidized Glutathione in Aqueous Urea Solution by All-Atom Molecular Dynamic Simulations and 2D-NOESY Spectrum

  • Published:
Journal of Solution Chemistry Aims and scope Submit manuscript

Abstract

All-atom molecular simulations and two-dimensional nuclear overhauser effect spectra have been used to study the conformations and interactions of oxidized glutathione (GSSG) in aqueous urea solution. The simulations were characterized by intramolecular distance, radius of gyration, solvent-accessible surface area, and root-mean-square deviation. Interestingly, the two chains connected by the GSSG disulfide linkage exhibited different flexibilities in the aqueous urea solution. GSSG can convert from “extended” to “folded” states in the simulations. Its preferred conformation in aqueous urea solutions is “extended”, which was confirmed by the 2D nuclear magnetic resonance (NMR) experiment. The two different types of amide hydrogen atoms in cysteine and glycine also showed different capacities to form N–H⋯O hydrogen bonds. The results were confirmed by temperature-dependent NMR experiment.

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

Scheme 1
Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Nur, E., Verwijs, M., Waart, D.R., Schnog, J.B., Otten, H., Brandjes, D.P., Biemond, B.J., Elferink, R.P.: Increased efflux of oxidized glutathione (GSSG) causes glutathione depletion and potentially diminishes antioxidant defense in sickle erythrocytes. BBA-Mol. Basis Dis. 1812, 1412–1417 (2011)

    Article  CAS  Google Scholar 

  2. Visioli, F., Wolfram, R., Richard, D., Abdullah, M.I.C., Crea, R.: Olive phenolics increase glutathione levels in healthy volunteers. J. Agric. Food Chem. 57, 1793–1796 (2009)

    Article  CAS  Google Scholar 

  3. Aliaga, M.E., López-Alarcón, C., García-Río, L., Martín-Pastor, M., Speisky, H.: Redox-changes associated with the glutathione-dependent ability of the Cu(II)–GSSG complex to generate superoxide. Bioorg. Med. Chem. 20, 2869–2876 (2012)

    Article  CAS  Google Scholar 

  4. Yap, L., Sancheti, H., Ybanez, M.D., Garcia, J., Cadenas, E., Han, D.: Chapter 6—Determination of GSH, GSSG, and GSNO using HPLC with electrochemical detection. Methods Enzymol. 473, 137–147 (2010)

    Article  CAS  Google Scholar 

  5. Wang, T., An, Y., He, H., Qian, D., Cai, R.: Simultaneous determination of oxidized and reduced glutathione in eel’s (monopterus albus) plasma by transient pseudoisotachophoresis coupled with capillary zone electrophoresis. J. Agric. Food Chem. 56, 368–373 (2008)

    Article  CAS  Google Scholar 

  6. Holland, R.A., Hawkins, E.A., Eggler, L., Mesecar, A.D., Fabris, D., Fishbein, J.C.: Prospective type 1 and type 2 disulfides of keap1 protein. Chem. Res. Toxicol. 21, 2051–2060 (2008)

    Article  CAS  Google Scholar 

  7. Haddad, J.J.: A redox microenvironment is essential for MAPK-dependent secretion of pro-inflammatory cytokines: modulation by glutathione (GSH/GSSG) biosynthesis and equilibrium in the alveolar epithelium. Cell. Immunol. 270, 53–61 (2011)

    Article  CAS  Google Scholar 

  8. Safavi, A., Maleki, N., Farjami, E., Mahyari, F.A.: Simultaneous electrochemical determination of glutathione and glutathione disulfide at a nanoscale copper hydroxide composite carbon ionic liquid electrode. Anal. Chem. 81, 7538–7543 (2009)

    Article  CAS  Google Scholar 

  9. Raturi, A., Mutus, B.: Characterization of redox state and reductase activity of protein disulfide isomerase under different redox environments using a sensitive fluorescent assay. Free Radic. Biol. Med. 43, 62–70 (2007)

    Article  CAS  Google Scholar 

  10. Hofstetter, D., Nauser, T., Koppenol, W.H.: Hydrogen exchange equilibria in glutathione radicals: rate constants. Chem. Res. Toxicol. 23, 1596–1600 (2010)

    Article  CAS  Google Scholar 

  11. Wang, X., Hai, C.X., Liang, X., Yu, S.X., Zhang, W., Li, Y.L.: The protective effects of Acanthopanax senticosus Harms aqueous extracts against oxidative stress: role of Nrf2 and antioxidant enzymes. J. Ethnopharmacol. 127, 424–432 (2010)

    Article  CAS  Google Scholar 

  12. Lu, D., Liu, Z.: Dynamic redox environment-intensified disulfide bond shuffling for protein refolding in vitro: molecular simulation and experimental validation. J. Phys. Chem. B 112, 15127–15133 (2008)

    Article  CAS  Google Scholar 

  13. Park, J., Jeong, J., Kim, J.: Destabilization of a bovine B12 trafficking chaperone protein by oxidized form of glutathione. Biochem. Biophys. Res. Commun. 420, 547–551 (2012)

    Article  CAS  Google Scholar 

  14. Shinichi, E., Hoffmann, M.R., Colussi, A.J.: Ozone oxidizes glutathione to a sulfonic acid. Chem. Res. Toxicol. 22, 35–40 (2009)

    Article  Google Scholar 

  15. Kim, S., Jung, H., Hyun, D., Park, E., Kim, Y., Lim, C.: Glutathione reductase plays an anti-apoptotic role against oxidative stress in human hepatoma cells. Biochimie 92, 927–932 (2010)

    Article  CAS  Google Scholar 

  16. Petzold, H., Sadler, P.J.: Oxidation induced by the antioxidantglutathione (GSH). Chem. Commun. 37, 4413–4415 (2008)

    Article  Google Scholar 

  17. McMahon, B.K., Gunnlaugsson, T.: Selective detection of the reduced form of glutathione (GSH) over the oxidized (GSSG) form using a combination of glutathione reductase and a Tb(III)–cyclen maleimide based lanthanide luminescent ‘switch on’ assay. J. Am. Chem. Soc. 134, 10725–10728 (2012)

    Article  CAS  Google Scholar 

  18. Krezel, A., Wójcik, J., Maciejczyk, M., Bal, W.: Zn(II) complexes of glutathione disulfide: structural basis of elevated stabilities. Inorg. Chem. 50, 72–85 (2011)

    Article  CAS  Google Scholar 

  19. Jihen, E.H., Fatima, H., Nouha, A., Baati, T., Imed, M., Abdelhamid, K.: Cadmium retention increase: a probable key mechanism of the protective effect of zinc on cadmium-induced toxicity in the kidney. Toxicol. Lett. 196, 104–109 (2010)

    Article  CAS  Google Scholar 

  20. Martín, S.F., Sawai, H., Villalba, J.M., Hannun, Y.A.: Redox regulation of neutral sphingomyelinase-1 activity in HEK293 cells through a GSH-dependent mechanism. Arch. Biochem. Biophys. 459, 295–300 (2007)

    Article  Google Scholar 

  21. Lampela, O., Juffer, A.H., Rauk, A.: Conformational analysis of glutathione in aqueous solution with molecular dynamics. J. Phys. Chem. A 107, 9208–9220 (2003)

    Article  CAS  Google Scholar 

  22. Kummli, D.S., Frey, H.-M., Leutwyler, S.: Accurate determination of the structure of 1,3,5-trifluorobenzene by femtosecond rotational Raman coherence spectroscopy and ab initio calculations. Chem. Phys. 367, 36–43 (2010)

    Article  CAS  Google Scholar 

  23. Endo, S., Fujimoto, A., Kumada, S., Matsunaga, T., Ohno, S., Mano, J., Tajima, K., El-Kabbani, O., Hara, A.: Modulation of activity and inhibitor sensitivity of rabbit aldose reductase-like protein (AKR1B19) by oxidized glutathione and SH-reagents. Chem. Biol. Interact. 202, 146–152 (2013)

    Article  CAS  Google Scholar 

  24. Guttmann, D., Poage, G., Johnston, T., Zhitkovich, A.: Reduction with glutathione is a weakly mutagenic pathway in chromium(VI) metabolism. Chem. Res. Toxicol. 21, 2188–2194 (2008)

    Article  CAS  Google Scholar 

  25. Campanali, A.A., Kwiecien, T.D., Hryhorczuk, L., Kodanko, J.J.: Oxidation of glutathione by [FeIV(O)(N4Py)]2+: characterization of an [FeIII(SG)(N4Py)]2+ intermediate. Inorg. Chem. 49, 4759–4761 (2010)

    Article  CAS  Google Scholar 

  26. Ellison, I., Richie, J.P.: Mechanisms of glutathione disulfide efflux from erythrocytes. Biochem. Pharmacol. 83, 164–169 (2012)

    Article  CAS  Google Scholar 

  27. Ballesteros, A., Jiang, P., Summerfelt, A., Du, X., Chiappelli, J., Donnell, P., Kochunov, P., Hong, L.E.: No evidence of exogenous origin for the abnormal glutathione redox state in schizophrenia. Schizophr. Res. 146, 184–189 (2013)

    Article  Google Scholar 

  28. Zhang, R., Meng, X., Huang, J., Wu, W.: Molecular dynamics simulations and NMR experimental study of oxidized glutathione in aqueous solution. J. Solution Chem. 41, 879–887 (2012)

    Article  CAS  Google Scholar 

  29. Das, A., Mukhopadhyay, C.: Atomistic mechanism of protein denaturation by urea. J. Phys. Chem. B 112, 7903–7908 (2008)

    Article  CAS  Google Scholar 

  30. Zang, R., Zhou, R., Berne, B.J.: Urea’s action on hydrophobic interactions. J. Am. Chem. Soc. 131, 1535–1541 (2009)

    Article  Google Scholar 

  31. Mark, P., Nilsson, L.: Structure and dynamics of the TIP3P, SPC, and SPC/E water models at 298 K. J. Phys. Chem. A 105, 9954–9960 (2001)

    Article  CAS  Google Scholar 

  32. Berweger, C.D., Gunsteren, W.F., Müller-Plathe, F.: Force field parametrization by weak coupling te-engineering SPC water. Chem. Phys. Lett. 232, 429–436 (1995)

    Article  CAS  Google Scholar 

  33. Jorgensen, W.L., Maxwell, D.S., Tirado-Rives, J.: Development and testing of the OPLS all-atom force field on conformational energetics and properties of organic liquids. J. Am. Chem. Soc. 118, 11225–11236 (1996)

    Article  CAS  Google Scholar 

  34. Jorgensen, W.L., Swenson, C.J.: Optimized intermolecular potential functions for amides and peptides. structure and properties of liquid amides. J. Am. Chem. Soc. 107, 569–578 (1985)

    Article  CAS  Google Scholar 

  35. Dudek, M.J., Ramnarayan, K., Ponder, J.W.: Protein structure prediction using a combination of sequence homology and global energy minimization: II. energy functions. J. Comput. Chem. 19, 548–573 (1998). http://dasher.wustl.edu/tinker. Accessed 18 Oct 2012

    Google Scholar 

  36. The PDB website is http://www.rcsb.org/pdb/. Accessed 18 Oct 2012

  37. Connolly, M.L.: Analytical molecular surface calculation. J. Appl. Crystallogr. 16, 548–558 (1983)

    Article  CAS  Google Scholar 

  38. Zheng, G., Stait-Gardner, T., Anil Kumar, P.G., Torres, A.M., Price, W.S.: PGSTE-WATERGATE: An STE-based PGSE NMR sequence with excellent solvent suppression. J. Magn. Reson. 191, 159–163 (2008)

    Article  CAS  Google Scholar 

  39. Clairac, R.P.L., Geierstanger, B.H., Mrksich, M., Dervan, P.B., Wemmer, D.E.: NMR characterization of hairpin polyamide complexes with the minor groove of DNA. J. Am. Chem. Soc. 119, 7909–7916 (1997)

    Article  Google Scholar 

  40. Lei, Y., Li, H., Zhang, R., Han, S.: Molecular dynamics simulations of biotin in aqueous solution. J. Phys. Chem. B. 108, 10131–10137 (2004)

    Article  CAS  Google Scholar 

  41. Uemura, K., Kitagawa, S., Fukui, K., Saito, K.: A contrivance for a dynamic porous framework: cooperative guest adsorption based on square grids connected by amide–amide hydrogen bonds. J. Am. Chem. Soc. 126, 3817–3828 (2004)

    Article  CAS  Google Scholar 

  42. Morgado, C.A., Hillier, I.H., Burton, N.A., McDouall, J.J.W.: A QM/MM study of fluoroaromatic interactions at the binding site of carbonic anhydrase II, using a DFT method corrected for dispersive interactions. Phys. Chem. Chem. Phys. 10, 2706–2714 (2008)

    Article  CAS  Google Scholar 

  43. Zhang, R., Wu, W.: Studies on the structures and interactions of glutathione in aqueous solution by molecular dynamics simulations and NMR spectroscopy. J. Mol. Liq. 162, 20–25 (2011)

    Article  CAS  Google Scholar 

  44. Schedlbauer, A., Coudevylle, N., Auer, R., Kloiber, K., Tollinger, M., Konrat, R.: Autocorrelation analysis of NOESY data provides residue compactness for folded and unfolded proteins. J. Am. Chem. Soc. 131, 6038–6039 (2009)

    Article  CAS  Google Scholar 

  45. Denkova, P.S., Lokeren, L., Verbruggen, I., Willem, R.: Self-aggregation and supramolecular structure investigations of triton X-100 and SDP2S by NOESY and diffusion ordered NMR spectroscopy. J. Phys. Chem. B 112, 10935–10941 (2008)

    Article  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by the National Natural Science Foundation of China (No. 20903026), the Talents Introduction Foundation for Universities of Guangdong Province(2011) and Scientific Research Foundation of the Natural Science Foundation of Guangdong Province, China (No. S2011010002483).

Author information

Authors and Affiliations

  1. Laboratory of Physical Chemistry, College of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, People’s Republic of China

    Rong Zhang, Guodong Huang, Wei Zeng & Wenjuan Wu

Authors
  1. Rong Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Guodong Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wei Zeng
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wenjuan Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rong Zhang.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOC 53 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhang, R., Huang, G., Zeng, W. et al. Conformations of Oxidized Glutathione in Aqueous Urea Solution by All-Atom Molecular Dynamic Simulations and 2D-NOESY Spectrum. J Solution Chem 42, 2229–2239 (2013). https://doi.org/10.1007/s10953-013-0097-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10953-013-0097-4

Keywords

Search

Navigation