Probing site specificity of DNA binding metallointercalators by NMR spectroscopy and molecular modeling

E. M. Proudfoot, J. P. Mackay, P. Karuso*

*Corresponding author for this work

Research output: Contribution to journalArticle

47 Citations (Scopus)

Abstract

The molecular recognition of oligonucleotides by chiral ruthenium complexes has been probed by NMR spectroscopy using the template Δ-cis-α- and Δ-cis-β-[Ru(RR-picchxnMe2) (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 picchxnMe2 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 Δ-cis-α,-[Ru(RR-picchxnMe2)(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 Δ-cis-β-[Ru(RR-picchxnMe2)(phen)]2+ complex with [d(CGCGATCGCG)]2 showed that the complex binds only weakly to the ends of the oligonucleotide. The interaction of Δ-cis-α-[Ru(RR-picchxnMe2)-(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, Δ-cis-α- and Δ-cis-β-[Ru-(RR-picchxnMe2)(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 ΔTm) 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.

Original languageEnglish
Pages (from-to)4867-4878
Number of pages12
JournalBiochemistry
Volume40
Issue number15
DOIs
Publication statusPublished - 17 Apr 2001

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