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Computational Studies of the Oxidation of Guanine

Computational Studies of the Oxidation of Guanine. Barbara H. Munk Computational Chemistry 6440/7440. Overview. Background Research Plan Results to date Next Steps Summary. Background.

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Computational Studies of the Oxidation of Guanine

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  1. Computational Studies of the Oxidation of Guanine Barbara H. Munk Computational Chemistry 6440/7440 Chem 6440/7440

  2. Overview • Background • Research Plan • Results to date • Next Steps • Summary Chem 6440/7440

  3. Background • Oxidation of nucleobases and nucleotides followed by strand scission of the DNA/RNA is a major pathway in mutagenesis, carcinogenesis, aging and cell death Burrows, C.J.; Muller, J.G.; Oxidative Nucleobase Modifications Leading to Strand Scission; Chem. Rev. 1998, 98, 1109-1151. Chem 6440/7440

  4. Background Burrows, C.J.; Muller, J.G.; Oxidative Nucleobase Modifications Leading to Strand Scission; Chem. Rev. 1998, 98, 1109-1151. Chem 6440/7440

  5. Background • Guanine has a lower redox potential than other nucleobases and chemical oxidation of this base is observed experimentally • Oxidants include reactive oxygen species, ionizing radiation, and transition metal complexes • Reactive oxygen species include: HO·, RO·, ROO·, and O2· Baik, M.H.; Silverman, J.S.; Yang, I.V.; Ropp, P.A.; Szalai, V.A.; Yang, W.; and Thorp, W.H.; Using Density Functional Theory to Design DNA Base Analogues with Low Oxidation Potentials; J. Phys. Chem. B.; 2001, 105, 6437-6444 Chem 6440/7440

  6. Background Nucleobase and Nucleoside Numbering Schemes Burrows, C.J.; Muller, J.G.; Oxidative Nucleobase Modifications Leading to Strand Scission; Chem. Rev. 1998, 98, 1109-1151. Chem 6440/7440

  7. Background Oxidation of guanine can occur at three sites Chem 6440/7440

  8. Background • Products formed by attack at C-4 and C-5 revert to guanine • Oxidation at C-8 leads to two forms of DNA damage Chem 6440/7440

  9. Background Chem 6440/7440

  10. Research Plan • Use a minimally substituted guanine structure • Evaluate oxidation at C-4, C-5 and C-8 positions with ·OH, ·OCH3, and ·OOH Chem 6440/7440

  11. Research Plan • Calculate the enthalpy and free energy of reaction, and forward and reverse barrier heights using Gaussian (Development Version) on Linux operating system • Electron correlation important • Use Density Functional Theory – B3LYP • Basis set – 6-31G(d) • Works well for organic molecules • Polarization functions give molecular flexibility Prat, F.; Houk, K.N.; Foote, C.S.; Effect of Guanine Stacking on the Oxidation of 8-Oxoguanine in B-DNA. J. Am. Chem. Soc. 1998, 120, 845-846. Sugiyama, H.; Saito, I.; Theoretical Studies of GG-Specific Photocleavage of DNA via Electron Transfer: Significant Loweering of Ionization potential and 5’ Localization of HOMO of Stacked GG Bases in B-Form DNA. J. Am. Chem. Soc. 1996, 118, 7063-7068. Chem 6440/7440

  12. Results to Date Chem 6440/7440

  13. Reactions with ·OH Chem 6440/7440 * To be determined

  14. 4-Hydroxyguanine transition state Guanine 4-Hydroxyguanine radical Chem 6440/7440

  15. 5-Hydroxyguanine transition state 5-Hydroxyguanine radical Guanine Chem 6440/7440

  16. Guanine 8-hydroxyguanine radical Chem 6440/7440

  17. Reactions with ·OCH3 Chem 6440/7440

  18. 4-Methoxyguanine transition state Guanine 4-Methoxyguanine radical Chem 6440/7440

  19. 5-Methoxyguanine transition state 5-Methoxyguanine radical Guanine Chem 6440/7440

  20. 8-Methoxyguanine transition state 8-Methoxyguanine radical Guanine Chem 6440/7440

  21. Reactions with ·OOH Chem 6440/7440 * To be determined

  22. 4-Hydroperoxy guanine complex Guanine 4-Epoxyguanine Chem 6440/7440

  23. Reactions with ·OOH Chem 6440/7440 * To be determined

  24. 5-Hydroperoxy guanine complex Guanine 5-Epoxyguanine Chem 6440/7440

  25. Reactions with ·OOH Chem 6440/7440 * To be determined

  26. 8-Hydroperoxy guanine complex 2,6-Diamino-5-formamido-4-hydroxy pyrimidine Guanine Chem 6440/7440

  27. Next Steps • Identify transition states for • 8-hydroxyguanine • 4, 5, and 8 hydroperoxyguanine • 4 and 5 epoxyguanine • 8-oxo-guanine • 2, 6-diamino-5-formamido-4-hydroxy pyrimidine (FAPy-G) Chem 6440/7440

  28. Summary • Oxidation by ·OH and ·OCH3 at the C-8 position appears to be thermodynamically more favorable than oxidation at C-4 and C-5 • Oxidation by ·OOH appears to be a multistep process • Oxidation at the C-4 and C-5 positions may proceed through an epoxide intermediate Chem 6440/7440

  29. Dr. H.B. Schlegel Schlegel Group Dr. Smriti Anand Dr. Hrant Hratchian Jie Li Stan Smith Funding Dept. of Chemistry, WSU NSF Gaussian Inc. Computer Time NCSA WSU- C&IT Acknowledgements Chem 6440/7440

  30. Reactions Generating·OH Chem 6440/7440

  31. Supplemental Material • Alkoxyl radicals RO· can be generated via radical ring opening of epoxides with a nickel catalyst or via hydroperoxides • ROO· are generated in vivo, as lipid hydroperoxides are produced as a consequence of cellular exposure to oxidative stress Chem 6440/7440

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