Chem 6440/7440 Computational Studies of the Oxidation of Guanine Barbara H. Munk Computational...
-
date post
20-Dec-2015 -
Category
Documents
-
view
218 -
download
0
Transcript of Chem 6440/7440 Computational Studies of the Oxidation of Guanine Barbara H. Munk Computational...
Chem 6440/7440
Computational Studies of the Oxidation of Guanine
Barbara H. MunkComputational Chemistry
6440/7440
Chem 6440/7440
Overview
Background Research Plan Results to date Next Steps Summary
Chem 6440/7440
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
Background
Burrows, C.J.; Muller, J.G.; Oxidative Nucleobase Modifications Leading to Strand Scission; Chem. Rev. 1998, 98, 1109-1151.
Chem 6440/7440
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
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
Background
Oxidation of guanine can
occur at three sites
Chem 6440/7440
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
Background
Chem 6440/7440
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
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
flexibilityPrat, 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
Results to Date
Chem 6440/7440
Reactions with ·OHEnthalpy
of Reaction (Kcal/mol)
Barrier Height
Forward (Kcal/mol)
Barrier Height
Reverse (Kcal/mol)
Free Energy of Reaction (Kcal/mol)
Barrier Height
Forward (Kcal/mol)
Barrier Height
Reverse (Kcal/mol)
4-hydroxyguanine -18.26 -1.62 16.64 -8.19 8.28 16.47
5-hydroxyguanine -13.67 -4.33 9.34 -3.98 5.41 9.37
8-hydroxyguanine -33.06 * * -23.61 * *
* To be determined
Chem 6440/7440
Guanine 4-Hydroxyguanine radical
4-Hydroxyguanine transition state
Chem 6440/7440
Guanine5-Hydroxyguanine
radical
5-Hydroxyguanine transition state
Chem 6440/7440
Guanine 8-hydroxyguanine radical
Chem 6440/7440
Reactions with ·OCH3
Enthalpy of
Reaction (Kcal/mol)
Barrier Height
Forward (Kcal/mol)
Barrier Height
Reverse (Kcal/mol)
Free Energy of Reaction (Kcal/mol)
Barrier Height
Forward (Kcal/mol)
Barrier Height
Reverse (Kcal/mol)
4-methoxyguanine -2.86 10.37 13.23 8.76 21.56 12.80
5-methoxyguanine 0.62 6.88 6.26 12.22 18.63 6.41
8-methoxyguanine -18.98 1.09 20.07 -7.34 12.13 19.47
Chem 6440/7440
Guanine 4-Methoxyguanine radical
4-Methoxyguanine transition state
Chem 6440/7440
Guanine5-Methoxyguanine
radical
5-Methoxyguanine transition state
Chem 6440/7440
Guanine
8-Methoxyguanine transition state
8-Methoxyguanine radical
Chem 6440/7440
Reactions with ·OOH
Enthalpy of
Reaction (Kcal/mol)
Barrier Height
Forward (Kcal/mol)
Barrier Height
Reverse (Kcal/mol)
Free Energy of Reaction (Kcal/mol)
Barrier Height
Forward (Kcal/mol)
Barrier Height
Reverse (Kcal/mol)
4-hydroperoxy
guanine complex
11.46 13.29 1.83 23.03 25.30 2.27
4-epoxyguanine 15.95 * * 18.44 * *
* To be determined
Chem 6440/7440
Guanine
4-Hydroperoxyguanine complex
4-Epoxyguanine
Chem 6440/7440
Reactions with ·OOHEnthalpy
of Reaction (Kcal/mol)
Barrier Height
Forward (Kcal/mol)
Barrier Height
Reverse (Kcal/mol)
Free Energy of Reaction (Kcal/mol)
Barrier Height
Forward (Kcal/mol)
Barrier Height
Reverse (Kcal/mol)
5-hydroperoxy
guanine complex
13.94 * * 25.60 * *
5-epoxyguanine 15.95 * * 18.44 * *
* To be determined
Chem 6440/7440
Guanine 5-Epoxyguanine
5-Hydroperoxyguanine complex
Chem 6440/7440
Reactions with ·OOHEnthalpy
of Reaction (Kcal/mol)
Barrier Height
Forward (Kcal/mol)
Barrier Height
Reverse (Kcal/mol)
Free Energy of Reaction (Kcal/mol)
Barrier Height
Forward (Kcal/mol)
Barrier Height
Reverse (Kcal/mol)
8-hydroperoxy
guanine complex
-5.94 * * 5.80
8-oxo-guanine * * * *
2,6-diamino-5-formamido-4-
hydroxy pyrimidine
0.71 * * 0.49 * *
* To be determined
Chem 6440/7440
Guanine 2,6-Diamino-5-formamido-4-
hydroxy pyrimidine
8-Hydroperoxyguanine complex
Chem 6440/7440
Next Steps
Identify transition states for8-hydroxyguanine4, 5, and 8 hydroperoxyguanine4 and 5 epoxyguanine8-oxo-guanine 2, 6-diamino-5-formamido-4-hydroxy
pyrimidine (FAPy-G)
Chem 6440/7440
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
Acknowledgements Dr. H.B. Schlegel Schlegel Group
Dr. Smriti AnandDr. Hrant HratchianJie LiStan Smith
Funding Dept. of Chemistry, WSU
NSF
Gaussian Inc.
Computer Time NCSA
WSU- C&IT
Chem 6440/7440
Reactions Generating ·OH
Chem 6440/7440
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