A model for the dynemicin-A cleavage of DNA using molecular dynamics simulation

Molecular dynamics (MD) simulations to model possible reaction pathways of the dynemicin-A-DNA cleavage mechanism were performed. Two base-pairs sequences, ApCpTpApCpTp-3'/TpGpApTpGpAp-5' and CpApCpGpGpGp-3'/GpTpGpCpCpCp-5', were considered in the calculations. A model based on a prior study of intercalation of dynemicin-A and posterior activation of the drug was assumed in this study. The minimum energy minor groove intercalation complexes for dynemicin-A were used as starting structures in the MD simulations for the reactive intermediate species involved in the postulated action mechanism. The dynemicin-A diol derivative product of the opening of the epoxy ring was used as a "steric mimic" ligand for the DNA-reactive diaryl intermediate. The calculated changes in the geometry of the intercalation complex, due to the opening of the epoxy ring, correspond to the approach of the postulated intermolecular reaction centers in the intercalation states that are responsible for the highest observed DNA cleavage frequency observed. Conversely, unfavorable reaction geometries were found for the intercalation modes corresponding to the lowest observed DNA cutting frequencies.