Mechanism of DNA threading intercalation of binuclear Ru complexes: uni- or bimolecular pathways depending on ligand structure and binding density

In the long succession of small transition-metal compounds interacting reversibly with DNA, semirigid binuclear ruthenium complexes stand out by displaying exceptionally slow binding kinetics. To reach the final intercalated state, one of the bulky metal centers has to be threaded through the base stack, leading to a high level of structural discrimination. This makes the idea of utilizing binuclear complexes interesting in applications involving DNA sequence or conformation recognition. The finding that threading intercalation of the two structural analogues, Lambda,Lambda-[mu-(11,11'-bidppz)X4Ru2]4+, X = 2,2'-bipyridine (Lambda,Lambda-B4) and X = 1,10'-phenanthroline (Lambda,Lambda-P4), into poly(dA-dT)2 can be described by surprisingly simple rate laws encouraged more extensive studies and analysis of these two systems. Kinetic measurements at different [basepair]/[complex] ratios show that Lambda,Lambda-B4 intercalates via a pseudo-first-order mechanism independent of binding density, whereas Lambda,Lambda-P4 displays a gradual transition from apparent first- to second-order kinetics when decreasing the [basepair]/[complex] mixing ratio. By employing the probabilistic method of McGhee and von Hippel, a rate law based on a supposed mechanism has been globally fitted and numerically integrated to describe threading of Lambda,Lambda-P4. In contrast to Lambda,Lambda-B4, the first-order mechanism of this analogue appears to require a long stretch of nonthreaded DNA. The results show that ancillary ligand structures indeed affect the mechanism of DNA threading, demonstrating the potential use of semirigid binuclear ruthenium complexes to target DNA.