Albany 2013: Book of Abstracts
June 11-15 2013
©Adenine Press (2012)
The Role of the Linker and Aromatic Pendent in Zn(II) Complexes for Recognition to Non-Canonical Thymine in DNA
It is challenging to design small molecules for the recognition of nucleic acid structural motifs such as bulges and loops. Ultimately, it is important to understand all of the energetic factors involved in binding including electrostatic interactions, hydrophobic transfer energetic, nucleic acid structural rearrangements as well as interactions between the nucleic acid and small molecule. We have recently reported the selective binding of Zn(II) macrocyclic complexes to DNA and RNA containing thymine or uracil bulges, respectively. The NMR structure of a DNA bulge alone and a DNA bulge with Zn(II) complex shows that the Zn(II) complex binds to the deprotonated N3 of thymine and the pendent aromatic stacks over the thymine in a pocket that abuts the major groove of the helix. Our current research focuses on understanding the role of the pendent aromatic group and the linker between macrocycle and aromatic group.
A single ring system was too small to stack on the thymine and led to weak binding, while a three ring system was more apt to intercalate into DNA, leading to poor selectivity. Pendents with two fused aromatic rings are optimal for bulge recognition. In addition, the presence of a heteroatom in the pendent aromatic group increases the polarity and electron deficiency of the pi system which promotes favorable stacking with the polar nucleobase. Studies are underway to better understand the importance of the linker and how it can affect recognition. It has been observed that a methylene linker works well when there is a binding pocket because it provides the flexibility for the aromatic pendent to slip into the pocket and stack tightly on the top of the nucleobase, as shown in the NMR structure below. (Fig. A) (Reprinted with permission from (1).Copyright (2012) American Chemical Society) In comparison, a less flexible sulfone linker doesn’t interact well with T-bulges which could be in part due to its inability to fit into the pocket. To better elucidate the linker trends and importance, direct attachment of a pendent to the macrocycle is being studied. The future application of this work is towards metal ion based optical sensors and nucleic acid conformational switches. .
del Mundo, I.M.A., et al., Inorg. Chemistry, 2012, 51(9) 5444-5457.
Stephanie A. Sander
Department of Chemistry