title: 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 BI and BII 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.
authors.affiliation: Institute of General Inorganic and Theoretical Chemistry, University of Innsbruck, Innrain 52a, A-6020 Innsbruck, Austria.
authors.forename: Michael
authors.initials: M
authors.lastname: Trieb
authors.forename: Christine
authors.initials: C
authors.lastname: Rauch
authors.forename: Bernd
authors.initials: B
authors.lastname: Wellenzohn
authors.forename: Fajar
authors.initials: F
authors.lastname: Wibowo
authors.forename: Thomas
authors.initials: T
authors.lastname: Loerting
authors.forename: Erwin
authors.initials: E
authors.lastname: Mayer
authors.forename: Klaus R
authors.initials: KR
authors.lastname: Liedl
mesh_terms: D001665:Binding Sites; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D004247:DNA / Q000737:chemistry / Q000187:drug effects*; D003630:Daunorubicin / Q000737:chemistry / Q000494:pharmacology*; D007364:Intercalating Agents / Q000494:pharmacology*; D008958:Models, Molecular; D009690:Nucleic Acid Conformation / Q000187:drug effects*; D013997:Time Factors
chemical_list: D007364:Intercalating Agents; D004247:DNA; D003630:Daunorubicin