First principles calculation of pK(a) 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 i onization 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 pr esence of two sites (N1 and N3) for ionization. We show that a procedure us ing first principles quantum mechanics (density functional theory with gene ralized gradient approximation, B3LYP, in combination with the Poisson-Bolt zmann 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.