First principles calculations of the tautomers and pKa values of 8-oxoguanine

Implications for mutagenicity and repair

Yun Hee Jang, William A. Goddard, Katherine T. Noyes, Lawrence Sowers, Sungu Hwang, Doo Soo Chung

Research output: Contribution to journalArticle

99 Citations (Scopus)

Abstract

8-Oxoguanine is a mutagenic oxidative damage product of guanine that has been the subject of many experimental studies. Despite numerous references to this damaged base, its precise configuration or population of configurations in equilibrium are unknown, as it can be drawn in over 100 potential neutral and ionized tautomeric forms. The structural uncertainty surrounding 8-oxoguanine complicates mechanistic studies of its mutagenicity and capacity to be recognized for repair. Experimental measurements on the tautomeric equilibria and pKa values of 8-oxoguanine are complicated by its insolubility in water. Therefore, we used first principles quantum mechanics (density functional theory, B3LYP, in combination with the Poisson-Boltzmann continuum-solvation model) to investigate the relative stabilities and site-specific pKa values of various neutral and ionized tautomers of 8-oxoguanine. We show that the major tautomer of neutral 8-oxoguanine in aqueous solution is the 6,8-diketo form 2, and that 8-oxoguanine has increased acidity at N1 relative to guanine. Our calculations on 2′-deoxyguanosine-3′,5′-bisphosphate and its 8-oxo analogue support the accepted conclusion that repulsion between the O8 of 8-oxoguanine and O5′ of the backbone sugar promote 8-oxoguanine: adenine pairings in the syn:anti conformation. Further, we show that the N7 proton of 8-oxoguanine is difficult to remove either through tautomerization or ionization, consistent with its involvement as an important landmark in distinguishing guanine from 8-oxoguanine. The possibility of additional structural landmarks that distinguish 8-oxoguanine from guanine, and a possible mechanism for glycosylase removal of 8-oxoguanine are discussed.

Original languageEnglish (US)
Pages (from-to)1023-1035
Number of pages13
JournalChemical Research in Toxicology
Volume15
Issue number8
DOIs
StatePublished - Aug 2002
Externally publishedYes

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Repair
Guanine
8-hydroxyguanine
Quantum theory
Solvation
Adenine
Mechanics
Acidity
Sugars
Uncertainty
Ionization
Density functional theory
Conformations
Protons
Solubility
Water

ASJC Scopus subject areas

  • Drug Discovery
  • Organic Chemistry
  • Chemistry(all)
  • Toxicology
  • Health, Toxicology and Mutagenesis

Cite this

First principles calculations of the tautomers and pKa values of 8-oxoguanine : Implications for mutagenicity and repair. / Jang, Yun Hee; Goddard, William A.; Noyes, Katherine T.; Sowers, Lawrence; Hwang, Sungu; Chung, Doo Soo.

In: Chemical Research in Toxicology, Vol. 15, No. 8, 08.2002, p. 1023-1035.

Research output: Contribution to journalArticle

Jang, Yun Hee ; Goddard, William A. ; Noyes, Katherine T. ; Sowers, Lawrence ; Hwang, Sungu ; Chung, Doo Soo. / First principles calculations of the tautomers and pKa values of 8-oxoguanine : Implications for mutagenicity and repair. In: Chemical Research in Toxicology. 2002 ; Vol. 15, No. 8. pp. 1023-1035.
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abstract = "8-Oxoguanine is a mutagenic oxidative damage product of guanine that has been the subject of many experimental studies. Despite numerous references to this damaged base, its precise configuration or population of configurations in equilibrium are unknown, as it can be drawn in over 100 potential neutral and ionized tautomeric forms. The structural uncertainty surrounding 8-oxoguanine complicates mechanistic studies of its mutagenicity and capacity to be recognized for repair. Experimental measurements on the tautomeric equilibria and pKa values of 8-oxoguanine are complicated by its insolubility in water. Therefore, we used first principles quantum mechanics (density functional theory, B3LYP, in combination with the Poisson-Boltzmann continuum-solvation model) to investigate the relative stabilities and site-specific pKa values of various neutral and ionized tautomers of 8-oxoguanine. We show that the major tautomer of neutral 8-oxoguanine in aqueous solution is the 6,8-diketo form 2, and that 8-oxoguanine has increased acidity at N1 relative to guanine. Our calculations on 2′-deoxyguanosine-3′,5′-bisphosphate and its 8-oxo analogue support the accepted conclusion that repulsion between the O8 of 8-oxoguanine and O5′ of the backbone sugar promote 8-oxoguanine: adenine pairings in the syn:anti conformation. Further, we show that the N7 proton of 8-oxoguanine is difficult to remove either through tautomerization or ionization, consistent with its involvement as an important landmark in distinguishing guanine from 8-oxoguanine. The possibility of additional structural landmarks that distinguish 8-oxoguanine from guanine, and a possible mechanism for glycosylase removal of 8-oxoguanine are discussed.",
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