Rare Tautomer Hypothesis Supported by Theoretical Studies: Ab Initio Investigations of Prototropic Tautomerism in the N-Methyl-P Base

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Abstract
Density functional theory calculations were applied to the prediction of the tautomeric properties of N-methyl-P (6-methyl-3,4-dihydro-8H-pyrimido[4,5-c][1,2]oxazin-7-one), a base of the nucleoside analogue dP (6-(2-deoxy-β-d-ribofuranosyl)-3,4-dihydro-8H-pyrimido[4,5-c][1,2]oxazin-7-one), for which water-solution experimental data have become available recently. The calculations have been performed for three tautomers in the gas phase, with various numbers of water molecules, and within the polarizable continuum model (PCM) of solvation. The obtained results correctly predict the presence of two tautomers and reproduce accurately the experimentally obtained ratio of the two most stable tautomeric forms when using a combination of explicit water molecules and the PCM of solvation. This lends additional support to the rare tautomer hypothesis of substitution mutagenesis in DNA replication.