Daunomycin Intercalation Stabilizes Distinct Backbone Conformations of DNA

Abstract

Daunomycin is a widely used antibiotic of the anthracycline family. In the present study we reveal the structural properties and important intercalator-DNA interactions by means of molecular dynamics. As most of the X-ray structures of DNA-daunomycin intercalated complexes are short hexamers or octamers of DNA with two drug molecules per doublehelix we calculated a self complementary 14-mer oligodeoxyribonucleotide duplex d(CGCGCGATCGCGCG)₂ in the B-form with two putative intercalation sites at the 5′- CGA-3′ step on both strands. Consequently we are able to look at the structure of a 1:1 complex and exclude crystal packing effects normally encountered in most of the X-ray crystallographic studies conducted so far. We performed different 10 to 20 ns long molecular dynamics simulations of the uncomplexed DNA structure, the DNA-daunomycin complex and a 1:2 complex of DNA-daunomycin where the two intercalator molecules are stacked into the two opposing 5′-CGA-3′ steps. Thereby—in contrast to X-ray structures—a comparison of a complex of only one with a complex of two intercalators per doublehelix is possible. The chromophore of daunomycin is intercalated between the 5′-CG-3′ bases while the daunosamine sugar moiety is placed in the minor groove. We observe a flexibility of the dihedral angle at the glycosidic bond, leading to three different positions of the ammonium group responsible for important contacts in the minor groove. Furthermore a distinct pattern of B_I and B_II around the intercalation site is induced and stabilized. This indicates a transfer of changes in the DNA geometry caused by intercalation to the DNA backbone.