Structure and energetics of clustered damage sites

Quantum calculations on duplex DNA trimers were used to model the changes in structure, hydrogen bonding, stacking properties, and electrostatic potential induced by oxidized purine bases and abasic (AP) sites. Results for oxidized purine bases were consistent with experimental data that show small structural and energetic perturbations induced by isolated 8-oxoguanine (8oG). Watson-Crick base pairing was preserved, and no major distortions of the backbone were induced. The thermal destabilization of DNA induced by 8oG was comparable to the energy of a single hydrogen bond. In contrast, AP sites caused substantial distortions of the DNA backbone that were accompanied by relocation of counterions. The loss of Watson-Crick hydrogen bonds in AP sites had the potential to destabilize DNA by 10-20 kcal/mol (0.4-0.8 eV); however, new inter- and intrastrand hydrogen bonds formed after removal of a nucleic acid base that significantly affected the energy of AP sites and introduced a strong dependence on sequence context. Quantum calculations on small DNA fragments provided starting conformations and force-field parameters for classical molecular dynamics simulations of radiation-induced single-strand breaks that most often combine hydrolysis of a phosphate-oxygen (P-O) bond with an AP site and fully or partially degraded sugar ring. P-O bond hydrolysis increased the freedom in backbone torsion angles, which allowed the broken strand to compress and partially fill the hole in the DNA created by the AP site. Results for strand breaks with a 3'phosphoglycolate were similar to those with phosphate end groups.