Probing site specificity of DNA binding metallointercalators by NMR spectroscopy and molecular modeling.
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.
Proudfoot
E M
EM
Department of Chemistry, Macquarie University, Sydney, NSW 2109, Australia.
Mackay
J P
JP
Karuso
P
P
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
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