Thermodynamics and kinetics of intramolecular water assisted proton transfer in Na+ -1-methylcytosine water complexes.

High-level ab initio predictions of the tautomerization equilibrium and rate constants of water-assisted proton transfer of 1-methyl-cytosine (MeC) to its MeC* imino tautomeric form in the presence of up to two water molecules (W) and the Na(+) cation were carried out. The calculated energy values were used to obtain the thermodynamic parameters and equilibrium concentration of MeC, its rare tautomer, and their complexes with up to two water molecules and the Na (+) cation. The rate constants for the tautomerization were obtained by using the instanton approach (a quasiclassical method based on the least-action principle). Hydration of MeC by one water molecule leads to an increase of the concentration of the MeC* tautomer in the equilibrium mixture and a decrease of the barrier of the MeC* formation (to 15.6 kcal/mol). If the Na(+) cation is present, the tautomeric form is much less favored, and the tautomerization barrier increases to 25.2 kcal/mol. It was found that MeC monohydrate has both the highest equilibrium (2.9 x 10(-2)) and rate (7.9 x 10(5) s(-1)) constants of tautomerization in comparison to the MeCNaW and MeCNa2W complexes containing the Na(+) cation. Moreover, this study also allows one to estimate the concentration of MeC present in the cell during DNA synthesis as the unwanted tautomer, which in forming a mismatched base pair can cause spontaneous point mutations. Kinetic simulations have demonstrated that the low values of equilibrium (10(-14)-10(-13)) and rate constants (10(-17)-10(-16) s(-1)) of tautomerization make contribution of the MeCNa(+)W and MeCNa(+)2W complexes to the point mutations in DNA unlikely. In contrast to these Na(+) complexes, MeC*W can reach an equilibrium concentration of 2.9 x 10(-2) within 10(-7) s; thus, it can increase the probability of the point mutations.