Structure of the complex of [Ru(tpm)(dppz)py](2+) with a B-DNA oligonucleotide - a single-substituent binding switch for a metallo-intercalator.
We report the synthesis of three new complexes related to the achiral [Ru(tpm)(dppz)py](2+) cation (tpm=tripyridazole methane, dppz=dipyrido[3,2-a:2',3'-c]phenazine, py=pyridine) that contain an additional single functional group on the monodentate ancillary pyridyl ligand. Computational calculations indicate that the coordinated pyridyl rings are in a fixed orientation parallel to the dppz axis, and that the electrostatic properties of the complexes are very similar. DNA binding studies on the new complexes reveal that the nature and positioning of the functional group has a profound effect on the binding mode and affinity of these complexes. To explore the molecular and structural basis of these effects, circular dichroism and NMR studies on [Ru(tpm)(dppz)py]Cl(2) with the octanucleotides d(AGAGCTCT)(2) and d(CGAGCTCG)(2), were carried out. These studies demonstrate that the dppz ligand intercalates into the G(2)-A(3) step, with {Ru(tpm)py} in the minor groove. They also reveal that the complex intercalates into the binding site in two possible orientations with the pyridyl ligand of the major conformer making close contact with terminal base pairs. We conclude that substitution at the 2- or 3-position of the pyridine ring has little effect on binding, but that substitution at the 4-position drastically disrupts intercalative binding, particularly with a 4-amino substituent, because of steric and electronic interactions with the DNA. These results indicate that complexes derived from these systems have the potential to function as sequence-specific light-switch systems.
Waywell
Philip
P
Department of Chemistry, University of Sheffield, Sheffield S3 7HF, UK.
Gonzalez
Veronica
V
Gill
Martin R
MR
Adams
Harry
H
Meijer
Anthony J H M
AJ
Williamson
Mike P
MP
Thomas
James A
JA
D001483:Base Sequence; D001665:Binding Sites; D002942:Circular Dichroism; D018360:Crystallography, X-Ray; D004247:DNA / Q000737:chemistry*; D004563:Electrochemistry; D007364:Intercalating Agents / Q000737:chemistry*; D008024:Ligands; D049449:Luminescence; D009682:Magnetic Resonance Spectroscopy; D008956:Models, Chemical; D015394:Molecular Structure; D009841:Oligonucleotides / Q000737:chemistry*; D009942:Organometallic Compounds / Q000737:chemistry*; D012428:Ruthenium / Q000737:chemistry*
D007364:Intercalating Agents; D008024:Ligands; D009841:Oligonucleotides; D009942:Organometallic Compounds; C549563:Ru(tripyridazole methane)(dipyrido(3,2-a-2',3'-c)phenazine)pyridine; D012428:Ruthenium; D004247:DNA