Theoretical study of the tandem cross-linkage lesion in DNA

The intramolecular radical cross-link reactions of 8,5′-cyclo-purines and 6,5′-cyclo-pyrimidines have been studied using the DFT B3LYP formalism with 6-31+G(d,p) and 6-311++G(d,p) basis sets, and including CPCM bulk solvation effects. In aqueous solution, the largest free energy barrier is 11.1 kcal/mol for dT^̇ → 6,5′-cycloT^̇ and the smallest 9.4 kcal/mol for dA^̇ → 8,5′-cycloA ^̇. Partial radical transfer occurs from the deoxyribose moiety to the connected base upon the formation of the transition structures. The unpaired spin density of the products is mainly localized on N7 in the 8,5′-cyclo-purines and on C5 in the 6,5′-cyclo-pyrimidines. The reaction free energies range from -4.3 kcal/mol (dC^̇→ 6,5′-cycloC^̇) to -9.7 kcal/mol (dG^̇ → 8,5′-cycloG^̇).