Book of Abstracts: Albany 2011

category image Albany 2011
Conversation 17
June 14-18 2011
©Adenine Press (2010)

Intercalation-Mediated Assembly and the Origin of Nucleic Acids

The continued increase of evidence for the central role of RNA in contemporary life seems to provide ever-increasing support for the RNA world hypothesis (1). However, it is difficult to imagine how RNA polymers would have appeared de novo, as the abiotic formation of long nucleic acid polymers from mononucleotides or short oligonucleotides presents several formidable challenges in the absence of highly evolved enzymes (2). For example, under solution conditions were the backbone linkages formed between mononucleotides or oligonucleotides are essentially irreversible very short cyclic products can be kinetically favored, which severely limits polymer growth. We are investigating the hypothesis that reversible non-covalent interactions between small planar molecules, similar to intercalating dye molecules, originally organized and selected the base pairs of nucleic acids (3). Recent experiments in our laboratory involving intercalation-mediated DNA and RNA ligation have confirmed that intercalators, which stabilize and rigidify nucleic acid duplexes, almost totally eliminate strand cyclization, allowing for chemical ligation of tetranucleotides into duplex polymers of up to 100 base pairs in length (4). In contrast, when these reactions are performed in the absence of intercalators, almost exclusively cyclic tetra- and octa- nucleotides are produced. Intercalator-free polymerization is not observed, even at tetranucleotide concentrations >10 000-fold greater than those at which intercalators enable polymerization. We have also observed that intercalation-mediated polymerization is most favored if the size of the intercalator matches that of the base pair; intercalators that bind to Watson–Crick base pairs promote the polymerization of oligonucleotides that form these base pairs. Additionally, intercalation-mediated polymerization is possible with an alternative, non-Watson–Crick-paired duplexes that selectively bind complementary intercalators. These results support the hypothesis that intercalators (acting as ‘molecular midwives’) could have facilitated the polymerization of the first nucleic acids and possibly helped select the first base pairs, even if only trace amounts of suitable oligomers were available. In another set of experiments, we are exploring the utility of reversible backbone linkages to facilitate nucleic acid polymer growth. Results from these experiments demonstrate how reversible linkages and intercalation can work together to promote the formation of extremely long polymers by the assembly and “recycling” of previously cyclized oligonucleotides.

This research was supported by the NSF and the NASA Astrobiology Center for Chemical Evolution (CHE-1004570) and the NASA Exobiology Program (NNX08A014G).


  1. R. F. Gesteland, T. R. Cech, J. F. Atkins, Eds., The RNA World, Cold Spring Harbor Laboratory Press, 3rd Ed (2006).
  2. A. E. Engelhart and N. V. Hud, Primitive genetic polymers, in Origins of Cellular Life, D. Deamer and J. Szostak, Eds., Cold Spring Harbor Laboratory Press (2010).
  3. N. V. Hud, S. S. Jain, X. Li, D. G. Lynn, Chem Biodiver 4, 768-783 (2007).
  4. E. D. Horowitz, A. E. Engelhart, M. C. Chen, K. A. Quarles, M. W. Smith, D. G. Lynn and N. V. Hud, Proc Natl Acad Sci USA 107, 5288-5293 (2010).

Aaron E. Engelhart
Ragan Buckley
Eric D. Horowitz
Nicholas V. Hud

School of Chemistry and Biochemistry
Center for Chemical Evolution
Georgia Institute of Technology
Atlanta, GA 30332 USA

Ph: (404) 385-1162
Fx: (404) 894-2295