Molecular dynamics simulations on binding models of Dervan-type polyamide + Cu(II) nuclease ligands to DNA

Molecular dynamics simulations for the ligand [Cu(BPA)](2+) (BPA = bis(2-pyridylmethyl)amine) nuclease bound to either the single-chain polyamide, ImPyImImPybetaDp, or the antiparallel double-polyamide, (ImImImbetaDp)(2), and associated with DNA were performed to predict the improvement of selective DNA cleavage ability of copper-based chemical nucleases. The results from the simulations indicate that either polyamide-bound [Cu(BPA)](2+) + OOH(-) (which is a necessary substrate in the redox mechanism of DNA cleavage) can locate in the minor groove of DNA in the parallel orientation similar to the X-ray structure. As a consequence of the polyamide + [Cu(BPA)](2+) + OOH(-) ligand binding to DNA, the active end oxygen atom of the OOH(-) substrate is held in close proximity to the known target C1'H or C4'H protons of the DNA. Upon examinations of six different ligands binding to DNA, the binding interaction of the entire ligand with DNA for each polyamide increases with the presence of [Cu(BPA)](2+) + OOH(-) ligand. The N-H groups of the linking regions from polyamide play an important role for the interaction by functioning as H-bond donors to N or O atoms of the nucleobase located on the floor of the minor groove of DNA. The investigation provides the feasible protocol to improve the selective DNA cleavage activity of chemical nucleases assisted by DNA recognition agents.