The Influence of 5′,8-Cyclo-2′-Deoxyguanosine on ds-DNA Charge Transfer Depends on Its Diastereomeric Form: A Theoretical Study

The genetic information stored in the nucleobase sequence is continuously exposed to harmful extra- and intra-cellular factors, which can lead to different types of DNA damage, with more than 70 lesion types identified so far. In this article, the influence of a multi-damage site containing (5′R/S) 5′,8-cyclo-2′-deoxyguanosine (cdG) and 7,8-dihydro-8-oxo-2′-deoxyguanosine ((OXO)dG) on charge transfer through ds-DNA was taken into consideration. The spatial geometries of oligo-RcdG: d[A(1)(5′R)cG(2)A(3)(OXO)G(4)A(5)]*d[T(5)C(4)T(3)C(2)T(1)] and oligo-ScdG: d[A(1)(5′S)cG(2)A(3)(OXO)G(4)A(5)]*d[T(5)C(4)T(3)C(2)T(1)] were optimized at the M06-2X/6-D95**//M06-2X/sto-3G level of theory in the aqueous phase using ONIOM methodology. For all the electronic property energies under discussion, the M06-2X/6-31++G** level of theory was used. Additionally, the non-equilibrated and equilibrated solvent-solute interactions were into consideration. The obtained results confirm the predisposition of (OXO)dG to radical cation formation regardless of the presence of other lesions in a ds-DNA structure. In the case of electron transfer, however, the situation is different. An excess electron migration towards (5′S)cdG was found to be preferred in the case of oligo-ScdG, while in the case of oligo-RcdG, (OXO)dG was favored. The above observation was confirmed by the charge transfer rate constant, vertical/adiabatic ionization potential, and electron affinity energy values, as well as the charge and spin distribution analysis. The obtained results indicate that 5′,8-cyclo-2′-deoxyguanosine, depending on the C5′ atom chirality, can significantly influence the charge migration process through the double helix. The above can be manifested by the slowdown of DNA lesion recognition and removal processes, which can increase the probability of mutagenesis and subsequent pathological processes. With regard to anticancer therapy (radio/chemo), the presence of (5′S)cdG in the structure of formed clustered DNA damage can lead to improvements in cancer treatment.