First principles calculation of pKa values for 5-substituted uracils

Oxidation of uracil (U) and thymine (5-Me-U) are believed to play a role in genetic instability because of the changes these oxidations cause in the ionization constants (pK(a) values), which in turn affects the base pairing and hence coding. However, interpretation of the experimental evidence for the changes of pK(a) with substitution at LT has been complicated by the presence of two sites (N1 and N3) for ionization. We show that a procedure using first principles quantum mechanics (density functional theory with generalized gradient approximation, B3LYP, in combination with the Poisson-Boltzmann continuum-solvation model) predicts such pK(a) values for a series of 5-substituted uracil derivatives in excellent correlation with experiment. In particular, this successfully resolves which cases prefer ionization at N1 and N3. Such first principles predictions of ionization constant should be useful for predicting and interpreting pK(a) for other systems.