The 2Ih and (OXO)G Proximity Consequences on Charge Transfer through ds-DNA: Theoretical Studies of Clustered DNA Damage

Genetic information is continuously exposed to harmful factors, both intra- and extracellular. Their activity can lead to the formation of different types of DNA damage. Clustered lesions (CDL) are problematic for DNA repair systems. In this study, the short ds-oligos with a CDL containing (R) or (S) 2Ih and (OXO)G in their structure were chosen as the most frequent in vitro lesions. In the condensed phase, the spatial structure was optimized at the M062x/D95**:M026x/sto-3G level of theory, while the electronic properties were optimized at the M062x/6-31++G** level. The influence of equilibrated and non-equilibrated solvent-solute interactions was then discussed. It was found that the presence of (R)2Ih in the ds-oligo structure causes a greater increase in structure sensitivity towards charge adoption than (S)2Ih, while (OXO)G shows high stability. Moreover, the analysis of charge and spin distribution reveals the different effects of 2Ih diastereomers. Additionally, the adiabatic ionization potential was found as follows for (R)-2Ih and (S)-2Ih in eV: 7.02 and 6.94. This was in good agreement with the AIP of the investigated ds-oligos. It was found that the presence of (R)-2Ih has a negative influence on excess electron migration through ds-DNA. Finally, according to the Marcus theory, the charge transfer constant was calculated. The results presented in the article show that both diastereomers of 5-carboxamido-5-formamido-2-iminohydantoin should play a significant role in the CDL recognition process via electron transfer. Moreover, it should be pointed out that even though the cellular level of (R and S)-2Ih has been obscured, their mutagenic potential should be at the same level as other similar guanine lesions found in different cancer cells.