Photoinduced charge separation and DNA self-repair depend on sequence directionality and stacking pattern

Charge separation is one of the most common consequences of the absorption of UV light by DNA. Recently, it has been shown that this process can enable efficient self-repair of cyclobutane pyrimidine dimers (CPDs) in specific short DNA oligomers such as the GAT00000000000000000000000000000000111111110000000011111111000000000000000000000000T sequence. The mechanism was characterized as sequential electron transfer through the nucleobase stack which is controlled by the redox potentials of nucleobases and their sequence. Here, we demonstrate that the inverse sequence TTAG promotes self-repair with higher quantum yields (0.58 +/- 0.23%) than GATT (0.44 +/- 0.18%) in a comparative study involving UV-irradiation experiments. After extended exposure to UV irradiation, a photostationary equilibrium between self-repair and damage formation is reached at 33 +/- 13% for GATT and at 40 +/- 16% for TTAG, which corresponds to the maximum total yield of self-repair. Molecular dynamics and quantum mechanics/molecular mechanics (QM/MM) simulations allowed us to assign this disparity to better stacking overlap between the G and A bases, which lowers the energies of the key A-G+ charge transfer state in the dominant conformers of the TTAG tetramer. These conformational differences also hinder alternative photorelaxation pathways of the TTAG tetranucleotide, which otherwise compete with the sequential electron transfer mechanism responsible for CPD self-repair. Overall, we demonstrate that photoinduced electron transfer is strongly dependent on conformation and the availability of alternative photodeactivation mechanisms. This knowledge can be used in the identification and prediction of canonical and modified DNA sequences exhibiting efficient electron transfer. It also further contributes to our understanding of DNA self-repair and its potential role in the photochemical selection of the most photostable sequences on the early Earth. The exposure of DNA to UV light may result in electron transfer between the bases. It can entail self-repair of common DNA lesions and the efficiency of these two processes is controlled by stacking overlap of the nucleobases.