Role of the Moiety Chirality in Determining the DNA Binding Characteristics of Threading Intercalators

Övrigt konferensbidrag, 2016

Small molecules that bind to DNA by threading their ancillary motifs through the DNA bases to intercalate their middle planar section between the DNA base pairs are known as threading intercalators. These molecules in general exhibit incredibly slow kinetics and high binding affinity, which puts them in the class of prospective anti-cancer drugs. We have been exploring a variety of ruthenium based threading intercalators using optical tweezers. In an optical tweezers set-up a single DNA molecule is attached between two polystyrene beads and manipulated in the presence of various concentrations of intercalators to characterize their DNA binding properties. In this study we explore the binding of two binuclear ruthenium complexes LL[m-bidppz(phen)4Ru2]4þ (LL-P) and DD-[m-bidppz(bipy)4Ru2]4þ (DD-B) in order to compare them with a previously studied sister molecule DD-P. All three molecules have the same middle intercalating dppz component that interacts with the DNA and only their ancillary side chains are varied. DD-P and LL-P have the same side chain with different chirality, while on the other hand DD-P and DD-B have the same chirality but vary in the size of the side chain. These intercalators are introduced to the system at different concentrations, while a single DNA molecule is held at a constant force. Measurements of DNA extension as a function of time provide the DNA equilibrium binding affinity and binding kinetics for these molecules. Preliminary data analysis suggests that LL-P and DD-B exhibit noticeably fast binding kinetics compared to the very similar DD-P. The equilibrium binding profile of the LL-P and DD-B complexes reveals that the dissociation constants are on the same order of magnitude as DD-P. These complexes have the same chemical structure in the middle intercalating part, which explains the similar affinity for all three of them and the difference in their chirality and size explains the difference in the kinetics of their approach to the final threaded intercalation state.