Enantioselective DNA Threading Dynamics by Phenazine-Linked [Ru(phen)2dppz]2+ Dimers

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Abstract
The interactions between the stereoisomers of the chiral bis-intercalator [μ-C4(cpdppz)2-(phen)4Ru2]4+ and DNA reveal interesting dynamic discrimination properties. The two enantiomers Δ-Δ and Λ-Λ both form very strong complexes with calf thymus DNA with similar thermodynamic affinities. By contrast, they display considerable variations in their binding kinetics. The Δ-Δ enantiomer has higher affinity for calf thymus DNA than for [poly(dA-dT)]2, and the association kinetics of the dimer to DNA, as well as to polynucleotides, requires a multiexponential fitting function. The dissociation reaction, on the other hand, could be described by a single exponential for [poly(dA-dT)]2, whereas two exponentials were required for mixed-sequence DNA. To understand the key mechanistic steps of the reaction, the kinetics was studied at varied salt concentration for different choices of DNA and chirality of the threading complex. The enantiomers were found to have markedly different dissociation rates, the Λ-Λ enantiomer dissociating about an order of magnitude faster than the Δ-Δ enantiomer. Also, the salt dependence of the dissociation rate constants differed between the enantiomers, being stronger for the Λ-Λ enantiomer than for the Δ-Δ enantiomer. Since the dissociation reaction requires unthreading of bulky parts of the bis-intercalator through the DNA helix, a considerable conformational change of the DNA must be involved, possibly defining the rate-limiting step.