AT‐Specific DNA Binding of Binuclear Ruthenium Complexes at the Border of Threading Intercalation

Abstract

The binuclear ruthenium complex [μ-bidppz(phen)(4)Ru(2)](4+) has been extensively studied since the discovery of its unusual threading intercalation interaction with DNA, a binding mode with extremely slow binding and dissociation kinetics. The complex has been shown to be selective towards long stretches of alternating AT base pairs, which makes it interesting, for example, as a model compound for anti-malaria drugs due to the high AT content of the genome of the malaria parasite P. falciparum. We have investigated the effect of bridging ligand structure on threading intercalation ability and found that length and rigidity as well as the size of the intercalated ring system are all factors that affect the rate and selectivity of the threading intercalation. In particular, we discovered a new DNA-threading compound, [μ-dppzip(phen)(4)Ru(2)](4+), which appears to be just at the border of being capable of threading intercalation and displays even greater selectivity for AT-DNA than the parent compound, [μ-bidppz(phen)(4)Ru(2)](4+).

DNA intercalation optimized by two-step molecular lock mechanism

“…The obtained equilibrium elastic properties of the saturated DNA-Pi complex, including its contour length, persistence length, and elastic modulus, are comparable to values of these parameters previously measured for threading intercalators2324. Figure 4A also shows the effects of aggregation on the DNA stretching curves, which can only be observed at high concentrations when holding DNA at very low initial extensions, comparable to bulk experimental conditions, which also observed aggregation15. During the first DNA stretch in the presence of ligand in solution on the time scale of ~100 s, the DNA elongation due to initial fast intercalation is observed, but the final state is not reached even after several consecutive stretch and release cycles.…”

“…This intercalative conversion is characterized for the rotationally flexible binuclear ruthenium complex [μ-bipb(phen) 4 Ru 2 ] 4+ (Pi) shown in Fig. 1B1516. Considering the structure of Pi, note that it has the same bulky side groups in a similar right-handed Δ chirality as for the previously reported threading mono-intercalator P5 and threading bis-intercalator Pc11, but it has a different bridging moiety (Fig.…”

“…showed that Pi elongates DNA16, but linear dichroism (LD) experiments by Andersson et al . found that the DNA-Pi complex does not preserve the free-DNA orientation, in contrast to conventional intercalators15. In addition, a ligand/base-pair ratio of 1:10 resulted in complete DNA condensation, limiting the ability of bulk experiments to characterize the Pi-DNA intercalation mechanism15.…”

“…Strong DNA condensation by cationic ligands with high affinity to DNA poses a great challenge in bulk experiments1517. However, in single molecule experiments the ends of the DNA molecule are pulled apart, preventing the molecule from dropping out of solution when condensed, and preventing condensation at high pulling forces18.…”

Interaction of metal complexes with nucleic acids

“…8a) can interact with DNA via a threading intercalation. 54 The degree of binding is dependent on the nature of the bridging ligand with the shorter bridging ligand impairing threading intercalation. It was also shown that [m-dppzip(phen) 4 Ru 2 ] 4+ displays high selectivity for DNA sequences with long stretches of alternating ATs.…”