Structural investigation of the hedamycin: D(ACCGGT)₂complex by NMR and restrained molecular dynamics

Hedamycin, a member of the pluramycin family of drugs, displays a range of biological responses including antitumor and antimicrobial activity. The mechanism of action is via direct interaction with DNA through intercalation between the bases of the oligonucleotide and alkylation of a guanine residue at 5′-PyG-3′ sites. There appears to be some minor structural differences between two earlier studies on the interaction of hedamycin with 5′-PyG-3′ sites. In this study, a high-resolution NMR analysis of the hedamycin:d(ACCGGT)2 complex was undertaken in order to investigate the effect of replacing the thymine with a guanine at the preferred 5′-CGT-3′ site. The resultant structure was compared with earlier work, with particular emphasis placed on the drug conformation. The structure of the hedamycin:d(ACCGGT)₂ complex has many features in common with the two previous NMR structures of hedamycin:DNA complexes but differed in the conformation and orientation of the N, N-dimethylvancosamine saccharide of hedamycin in one of these structures. The preferential binding of hedamycin to 5′-CG-3′ over 5′-TG-3′ binding sites is explained in terms of the orientation and location of the N, N-dimethylvancosamine saccharide in the minor groove.