title: Probing site specificity of DNA binding metallointercalators by NMR spectroscopy and molecular modeling.
abstract: The molecular recognition of oligonucleotides by chiral ruthenium complexes has been probed by NMR spectroscopy using the template Delta-cis-alpha- and Delta-cis-beta-[Ru(RR-picchxnMe(2)) (bidentate)](2+), where the bidentate ligand is one of phen (1,10-phenanthroline), dpq (dipyrido[3,2-f:2',3'-h]quinoxaline), or phi (9,10-phenanthrenequinone diimine) and picchxnMe(2)() is N,N'-dimethyl-N,N'-di(2-picolyl)-1,2-diaminocyclohexane. By varying only the bidentate ligand in a series of complexes, it was shown that the bidentate alone can alter binding modes. DNA binding studies of the Delta-cis-alpha-[Ru(RR-picchxnMe(2))(phen)](2+) complex indicate fast exchange kinetics on the chemical shift time scale and a "partial intercalation" mode of binding. This complex binds to [d(CGCGATCGCG)](2) and [d(ATATCGATAT)](2) at AT, TA, and GA sites from the minor groove, as well as to the ends of the oligonucleotide at low temperature. Studies of the Delta-cis-beta-[Ru(RR-picchxnMe(2))(phen)](2+) complex with [d(CGCGATCGCG)](2) showed that the complex binds only weakly to the ends of the oligonucleotide. The interaction of Delta-cis-alpha-[Ru(RR-picchxnMe(2))(dpq)](2+) with [d(CGCGATCGCG)](2) showed intermediate exchange kinetics and evidence of minor groove intercalation at the GA base step. In contrast to the phen and dpq complexes, Delta-cis-alpha- and Delta-cis-beta-[Ru(RR-picchxnMe(2))(phi)](2+) showed evidence of major groove binding independent of the metal ion configuration. DNA stabilization induced by complex binding to [d(CGCGATCGCG)](2) (measured as DeltaT(m)) increases in the order phen < dpq and DNA affinity in the order phen < dpq < phi. The groove binding preferences exhibited by the different bidentate ligands is explained with the aid of molecular modeling experiments.
authors: Department of Chemistry, Macquarie University, Sydney, NSW 2109, Australia.
authors: E M
authors: EM
authors: Proudfoot
authors: J P
authors: JP
authors: Mackay
authors: P
authors: P
authors: Karuso
mesh_terms: D001665:Binding Sites; D003035:Cobalt / Q000737:chemistry*; D004247:DNA / Q000737:chemistry*; D018736:DNA Adducts / Q000737:chemistry; D006358:Hot Temperature; D007364:Intercalating Agents / Q000737:chemistry*; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D009691:Nucleic Acid Denaturation; D009838:Oligodeoxyribonucleotides / Q000737:chemistry; D009942:Organometallic Compounds / Q000737:chemistry*; D010618:Phenanthrolines / Q000737:chemistry; D010847:Picolines / Q000737:chemistry*; D011725:Pyridines / Q000737:chemistry; D011810:Quinoxalines / Q000737:chemistry; D012428:Ruthenium / Q000737:chemistry*; D013237:Stereoisomerism; D013816:Thermodynamics
chemical_list: C104773:2,3-dipyridyl-6,7-dimethylquinoxaline; D018736:DNA Adducts; D007364:Intercalating Agents; D009838:Oligodeoxyribonucleotides; D009942:Organometallic Compounds; D010618:Phenanthrolines; D010847:Picolines; D011725:Pyridines; D011810:Quinoxalines; D003035:Cobalt; D012428:Ruthenium; D004247:DNA; C025205:1,10-phenanthroline