[Molecular mechanisms of mutations, arising during formation of 8-hydroxyguanine in DNA]

To reveal the molecular mechanisms of genotoxic effects of oxidation and irradiation, molecular mechanics computations were performed for double-helical olygonucleotides with 8-oxoguanine:adenine (OG.A) pairs in two configurations. Substitution of a T.A pair by OG(syn).A one results in minor changes of intramolecular interaction energy and of the conformational parameters of helixes. Nearly all the interproton distances in low-energy conformations of d(CCACTAOGTCACC):d(GGTGAATAGTGG) with a OG(syn).A pair are within the limits determined from NMR data. These results confirm the suggestion that such pairs can be formed in nucleic acid biosynthesis. The computations have shown that the interaction energies in the minima for duplexes with OG(anti).A and OG(syn).A pairs differ from one another by only 1 to 3 kcal/mol. This difference depends on the nucleotide context. These results allow one to suppose that the configuration of the OG.A pair in the double helix and, as a consequence, the induced mutation probability depends on interactions with its environment (neighboring base pairs and solvent).