Computational Study of the Formation of C8, C5 and C4 Guanine:Lysine Adducts via Oxidation of Guanine by Sulfate Radical Anion

Oxidative damage to DNA can lead to DNA–protein cross-links which can interfere with DNA transcription, replication, and repair. In experimental studies modeling oxidative damage to DNA, oxidation of guanosine by sulfate radical anion in the presence of lysine produced a mixture of lysine (Lys)-substituted spiroiminodihydantoins (Sp): ∼65% 5-Lys-Sp, ∼30% 8-Lys-Sp, and ∼5% 5,8-diLys-Sp. Pathways for formation of the lysine adducts during the oxidation of guanine by sulfate radical anions have been mapped out using B3LYP density functional theory and the SMD solvation model. Methylamine was used as a model for lysine, and imidazole served as a proton acceptor. The lowest barrier for methylamine reaction with guanine radical is addition at C8, yielding mainly 8-NHR-Sp and some 5,8-diNR-Sp. This is in good agreement with the cross-link ratios for mild oxidations mediated by type I photosensitizers such as benzophenone, but this is not in agreement with the product ratios for strong oxidants such as sulfate ra...