Book of Abstracts: Albany 2005
Controlling Nucleic Acid Assembly by Small Molecule Binding: Formation of Antiparallel (dA)n·(dA)n Duplexes in the Presence of Coralyne
For several decades the structures, binding specificity and dynamics of small molecule-DNA complexes have been studied with the goal of understanding the activity of small molecules in both the cause and treatment of cancer. Our laboratory is particularly interested in the potential for small molecules that intercalate nucleic acids to drive the assembly of secondary structures that are otherwise unstable in solution (1, 2). We have recently shown that coralyne, a small crescent-shaped molecule, promotes the formation of an anti-parallel duplex secondary structure from homo-adenine oligonucleotides (3). AFM studies reveal that the staggered alignment of homo-adenine oligonucleotides upon coralyne binding produces polymers of micrometers in length, but only 2 nm in height. The thermal stability of these assemblies is shown to depend upon length of the homo-adenine oligonucleotides. Dilution studies have revealed that the Kd of coralyne complex formation with the oligonucleotide d(A)16 is approximately 3 _M. In addition, we have investigated the binding of coralyne to a DNA duplex that contains eight sequential A·l;A mismatches between two flanking Watson-Crick helices. CD spectra confirm that coralyne binds to this mismatched duplex in the same manner as it does to homo-adenine oligonucleotides. Furthermore, the melting temperature of the mismatched duplex increases by 13°C in the presence of coralyne, whereas proflavine, another small intercalating molecule, increases the melting temperature of the same duplex by only 2°C. These results support the existence of a specific interaction between coralyne and A·A base pairs. These studies also demonstrate that the helical structure of the homo-adenine-coralyne duplex is compatible with the B-form DNA helix.
References and Footnotes
School of Chemistry and Biochemistry