TAUTOMERISM OF 1-METHYL DERIVATIVES OF URACIL, THYMINE, AND 5-BROMOURACIL - IS TAUTOMERISM THE BASIS FOR THE MUTAGENICITY OF 5-BROMOURIDINE

The tautomerism of the N-1-methylated derivatives of uracil, thymine, and 5-bromouracil has been studied in order to analyze its implication s in the mutagenicity of 5-bromouridine. The tautomeric preference in the gas phase was determined by means of state-of-the-art ab initio qu antum mechanical calculations. The influence of solvation in water on the tautomerism was examined by using ab initio self-consistent reacti on field and Monte Carlo free energy perturbation techniques. Finally, the effect of the DNA environment on the relative stability between t automers was estimated from Poisson-Boltzmann calculations. The theore tical results indicate that there are no relevant differences in the i ntrinsic tautomeric preference of the three pyrimidine bases. The cano nical oxo form is the main, if not the exclusive, form in the gas phas e. Indeed, neither solvation in water nor solvation in the duplex DNA changes sensibly the relative stability between tautomers. Therefore, our results provide a basis for ruling out the involvement of noncanon ical enol tautomers as the origin of the mutagenic properties of 5-bro mouridine.