Conversion of 5-hydroxy-8oxoguanine to guanidinohydantoin

Oxidative damage of DNA is closely related to mutagenesis, cancer, toxicity and aging. Because of the numerous interconnected pathways and the fleeting nature of the intermediates, oxidative damage to DNA is difficult to study experimentally. We have used computational chemistry explore the reaction mechanisms and elucidate the properties of the short-lived intermediates in guanine oxidation in collaboration with Prof. Cynthia Burrows at U. of Utah. Large changes in solvation energy on removal of a proton or an electron make it challenging to calculate pKa’s and redox potentials for biochemically relevant oxidation processes. We have developed a protocol using continuum solvation models with cavity scaling to calculate reliable pK_a’s and redox potentials for nucleobases and applied it to study the pK_a’s and redox potentials of nucleobases and intermediates in the oxidative degradation of guanine.

a. Munk, B. H.; Burrows, C. J.; Schlegel, H. B.; An Exploration of Mechanisms for the Transformation of 8-Hydroxy Guanine Radical to FAPyG by Density Functional Theory. Chem. Res. Toxicol. 2007, 20, 432-444 (10.1021/tx060187t).

b. Munk, B. H.; Burrows, C. J.; Schlegel, H. B.; Exploration of Mechanisms for the Transformation of 8-Oxoguanine to Guanidinohydantoin and Spirodihydantoin by Density Functional Theory. J. Am. Chem. Soc. 2008, 130, 5245-5256 (10.1021/ja7104448).

c. Psciuk, B. T.; Lord, R. L.; Munk, B. H.; Schlegel, H. B.; Theoretical Determination of One-Electron Oxidation Potentials for Nucleic Acid Bases. J. Chem. Theory Comput. 2012, 8, 5107−5123 (10.1021/ct300550x).

d. Psciuk, B. T.; Schlegel, H. B.; Computational Prediction of One-Electron Reduction Potentials and Acid Dissociation Constants for Guanine Oxidation Intermediates and Products. J. Phys. Chem. B 2013, 117, 9518–31 (10.1021/jp4062412).