Ab Initio Study of the Prototropic Tautomerism of Cytosine and Guanine and Their Contribution to Spontaneous Point Mutations

Abstract

High-level quantum-chemical and quantum-dynamics calculations are reported on the tautomerization equilibria and rate constants of isolated and monohydrated cytosine and guanine molecules. The results are used to estimate the fraction of the bases present in the cell during DNA synthesis as the unwanted tautomers that forms irregular base pairs, thus giving rise to a spontaneous GC → AT point mutation. A comparison of the estimated mutation frequencies with the observed frequency in E. coli is used to analyze two proposed mechanisms, differing in the degree of equilibration reached in the tautomerization reaction.It was found that the fraction of the rare tautomer in monohydrated complex of cytosine as well as guanine significantly exceed the amount responsible for the observed values of the GC → AT mutations. In the absence of water the equilibrium concentration of tautomeric forms is relatively large, but the barrier to their formation is high. It is possible that the mechanism in which a high tautomerization barrier keeps the tautomeric transformation far from a state of equilibrium is more likely than a mechanism in which water and/or polymerases produce a low equilibrium concentration of the tautomeric forms.

Water-mediated tautomerization of cytosine to the rare imino form: An ab initio dynamics study

“…Similar results were reported by Morpurgo et al [41] on the 1 to 3a tautomerization. Podolyan et al [42] discuss in detail the significance of the rare imino tautomer 3a for mutation, investigate the equilibrium between 1 and 3a and estimate the rate constant based on their ''instanton model". For the TS barrier they calculate values between 17 and 20 kcal mol À1 .…”

UV-Excitation from an Experimental Perspective: Frequency Resolved

“…The third channel with a lifetime of hundreds of picoseconds at 290 nm is proposed to involve excited-state tautomerization to a low-lying 1 nπ* state of the keto-imino tautomer 83 . The authors propose that in the condensed phase this channel would be quenched by rapid back hydrogen-transfer, catalyzed by hydrogen-bound water molecules 84,85 . Consequently this pathway would not alter the inherent photostability.…”

Theoretical study of valance photoelectron spectra of hypoxanthine, xanthine, and caffeine using direct symmetry‐adapted cluster/configuration interaction methodology

“…A number of mild stimulants are derived from XAN including caffeine (CAFF) and theobromine. 2,3 XAN is generated from HYP by XAN oxidoreductase, or it can be produced from guanine by guanine deaminase. CAFF is a crystalline XAN alkaloid, which is a psychoactive stimulant drug.…”