Anthracycline antibiotic arugomycin binds in both grooves of the DNA helix simultaneously: an NMR and molecular modelling study.
Perturbations to the 1H and 31P chemical shifts of DNA resonances together with twenty-four intermolecular nuclear Overhauser effects show that the anthracycline antibiotic arugomycin intercalates between the basepairs of the hexamer duplex d(5'-GCATGC)2 at the 5'-CpA and 5'-TpG binding sites. In the complex two drug molecules are bound per duplex with full retention of the dyad symmetry. Arugomycin adopts a threaded binding orientation with chains of sugars positioned in both the major and minor groove of the helix simultaneously. The complex is stabilized by hydrogen bonding, electrostatic and van der Waals interactions principally in the major groove and involving substituents on the rigidly oriented bicycloamino-glucose sugar of the antibiotic. A specific hydrogen bond is identified between the C2'-hydroxyl and the guanine N7 at the intercalation site. Together, interactions in the major groove appear to account for the intercalation specificity of arugomycin that requires both a guanine and thymine at the intercalation site. We are unable to identify any sequence specific interactions between the minor groove and the arugarose sugar (S1) which binds only weakly, through van der Walls contacts, over the d(GCA).d(TGC) trinucleotide sequence. The data indicate that the sugar chains of arugomycin are flexible and play little part in the interaction of the antibiotic with DNA. The intensity of sequential internucleotide NOEs identifies the intercalation site as being assymmetric. A family of conformers computed using restrained energy minimisation and molecular dynamics indicate that basepair buckling is a feature of the anthracycline intercalation site that may serve to maximise intermolecular van der Waals interactions by wrapping the basepairs around the antibiotic chromophore.
Searle
M S
MS
Molecular Pharmacology Group, Peter MacCallum Cancer Institute, Melbourne, Australia.
Bicknell
W
W
Wakelin
L P
LP
Denny
W A
WA
D018943:Anthracyclines; D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000378:metabolism*; D001483:Base Sequence; D002240:Carbohydrate Sequence; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D007364:Intercalating Agents / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D009692:Nucleic Acid Heteroduplexes; D010759:Phosphorus Isotopes; D011522:Protons
D018943:Anthracyclines; D000903:Antibiotics, Antineoplastic; D007364:Intercalating Agents; D009692:Nucleic Acid Heteroduplexes; D010759:Phosphorus Isotopes; D011522:Protons; C040037:arugomycin; D004247:DNA