Cation, solvent and small molecule interactions with nucleic acids

The three dimensional structure of nucleic acids, including the iconic DNA double helix, are the result of both their primary chemical structure and the interactions of these polymers with counter ions and solvent molecules. The negative charges that exist at each phosphate group along a nucleic acid backbone requires that cations in solution (e.g., sodium and magnesium ions) shield \ electrostatic repulsions that would otherwise prohibit the close approach of phosphate groups in secondary and higher order structures. We have a long-standing interest in the fundamental nature of cation association with DNA and RNA. Our research in this area has contributed to the overall understanding of the association of cations with DNA duplex and G-quadruplex structures. More recently, in collaboration with the laboratory of Loren D. Williams, we are using a combination of spectroscopic and chemical probing techniques to investigate the binding of divalent cations to RNA.

Solvent molecules, particularly water molecules, are also known to play a critical role in governing nucleic acid structures in vitro and in vivo. Motivated by desire to determine if water is absolutely necessary for the stability of nucleic acid secondary structures, and to investigate the hypothesis that RNA might have originated in a nonaqueous environment, we have recently demonstrated that three DNA and RNA structures (i.e., duplex, triplex and G-quadruplex structures) can exist in a water-free solvent that is comprised of urea and choline chloride (a so-called deep eutectic solvent). In addition to providing fundamental insights regarding the role of solvent molecules in determining nucleic acid structure, our demonstration that nucleic acid structures can be maintained in a deep eutectic solvent and a water-free ionic liquid supports the feasibility of investigating and using DNA nanotechnology in nonvolatile solvents.

In addition to cation and solvent interactions, we are also interested in understanding the binding of small molecules to nucleic acids, particularly molecules that bind through base pair intercalation. Studies conducted in our laboratory on this topic have provided fundamental insights regarding the thermodynamic origins of nucleic acid recognition through intercalation. These results important for our investigation of the molecular midwife hypothesis (discussed above), and have direct implications for understanding how a large class of therapeutic and carcinogenic molecules bind to DNA and RNA.

 Representative publications in this area:

Portella, G., Germann, M. W., Hud, N. V., and Orozco, M. (2014) MD and NMR analyses of choline and TMA binding to duplex DNA: on the origins of aberrant sequence-dependent stability by alkyl cations in aqueous and water-free solvents. J Am Chem Soc 136, 3075-3086.

Bowman, J. C., Lenz, T. K., Hud, N. V., and Williams, L. Dean (2012) Cations in charge: magnesium ions in RNA folding and catalysis. Curr Opin Struct Biol 22, 262-272.

Buckley, R., Enekwa, D.C., Williams, L.D. and Hud, N.V. (2011) Molecular recognition of Watson-Crick-like purine-purine base pairs. ChemBioChem 12, 2155-2158.

Mamajanov, I., Engelhart, A. E., Bean, H. D., Hud, N. V., (2010) DNA and RNA in Anhydrous Media: Duplex, Triplex, and G-Quadruplex Secondary Structures in a Deep Eutectic Solvent. Angew. Chem. Int. Ed. 49, 6310-6314.

Çetinkol, Ö. P., Hud, N. V. (2009) Molecular recognition of poly(A) by small ligands: An alternative method of analysis reveals nanomolar, cooperative and shape-selective binding, Nucleic Acids Res. 37, 611-621.

Horowitz, E.D., Lilavivat, S., Holladay, B.W., Germann, M.W., Hud, N.V. (2009) Solution Structure and Thermodynamics of 2',5' RNA Intercalation, J. Am. Chem. Soc. 131, 5716-6036.