Molecular mechanics and molecular dynamics studies of the intercalation of dynemicin-A with oligonucleotide models of DNA.

Intermolecular molecular modeling calculations to determine the intercalation behavior of dynemicin-A with DNA were performed using both static scanning and energy minimization and molecular dynamics relaxation techniques. Two base pair sequences, CpApCpGpGpGp-3'/GpTpGpCpCp-5' and ApCpTpApCpTp-3'/TpGpApTpGpAp-5', were considered in the calculations. The static scanning and energy minimization analyses identified multiple stable intercalation complexes for each base pair sequence. These complexes were subsequently used as starting structures in molecular dynamics relaxation simulations. Intercalation into the minor groove is preferred for both base pair sequences, and intercalation at a central CG site is preferred by about 9 kcal/mol over a TA site. However, intercalation at a TA site should be more reactive, in terms of chain scission, than that at a CG site, because dynemicin-A has more flexibility to achieve an intercalation geometry disposed to chemically react toward a base adjacent to the 3' side of a purine. This reaction model is consistent with experimental data.