Mutagenic properties of 5-halogenuracils:: Correlated quantum chemical ab initio study

The relative stability of all possible 5-bromouracil tautomers was studied theoretically in a gas phase, in a microhydrated environment (with one water molecule), and in bulk water. Tautomer structures were determined by gradient optimization at the correlated ab initio quantum chemical level with an extended basis set of atomic orbitals. The role of water was examined by using a self-consistent reaction field method. The relative stabilization and free energies in the gas phase, the microhydrated environment, and the bulk water clearly support the preference of the canonical keto form of 5-bromouracil in all mentioned environments. An increased abundance of enol tautomers when passing from uracil to 5-bromouracil is not supported by our calculations. Thus, the tautomeric model of the mutagenic activity of 5-bromouracil proposed previously [Hu et al. Biochemistry (2004) 43, 636 1] can be refuted. The validity of other mutagenic models was also discussed, and finally a new mechanism for explaining the mutagenic activity of halogenuracils based on their different behaviors in triplet excited states was suggested.