Life is widely believed to have evolved from a far simpler, self-replicating molecular system. However, the origin of the informational biopolymers (i.e. proteins, RNA, DNA) and the evolutionary path that led to early life remains obscure. The RNA world hypothesis posits that a hypothetical period once existed when information storage (genetics) and chemical catalysis (enzymatic activity) was once solely, or more heavily, the responsibility of RNA, before the advent of DNA and coded protein synthesis. A persistent challenge to this hypothesis is the lack of a plausible prebiotic pathway for the spontaneous formation of RNA polymers. We are investigating the possible origins of the chemical building blocks of RNA, and the hypothesis that RNA is largely the result of evolution – the descendant of an ancestral RNA-like polymer that had a different backbone and different nucleobases, a polymer that was much easier to assemble than present day RNA. As part of this research, we have demonstrated that glyoxylate, an organic analog of phosphate, forms linkages more easily when heated with unactivated nucleosides than phosphate, a result that supports the possibility that RNA once contained a completely organic backbone. We have demonstrated that multiple heterocyclic molecules, closely related to the nucleobases of contemporary RNA, will spontaneously form nucleosides with ribose, a result which supports the hypothesis that “the nucleoside problem” may not have been such a difficultly for the origin of RNA if other nucleobases were utilized by the first RNA-like polymers. Most recently, we have begun to explore the possible structure of proto-RNA and proto-polypeptide backbones. That is, the possible structure of the original backbones of these informational biopolymers, prior to what we hypothesize to have been multiple steps of structural refinement by chemical and/or biological evolution. Much of our work regarding the origin and evolution of RNA and polypeptides is being conducted in collaboration with other laboratories of the NSF-NASA Center for Chemical Evolution.
Representative publications in this area:
J. G. Forsythe, Yu, S.-S., Mamajanov, I., Grover, M. A., Krishnamurthy, R., Fernández, F. M., and Hud, N. V. (2015) Ester-Mediated Amide Bond Formation Driven by Wet-Dry Cycles: A Possible Path to Polypeptides on the Prebiotic Earth, Angew. Chem. Int. Ed. Engl. 54, 9871-9875.
I. Mamajanov, MacDonald, P. J., Ying, J., Duncanson, D. M., Dowdy, G. R., Walker, C. A., Engelhart, A. E., Fernandez, F. M., Grover, M. A., Hud, N. V., and F. Schork, J. (2014) Ester Formation and Hydrolysis during Wet–Dry Cycles: Generation of Far-from-Equilibrium Polymers in a Model Prebiotic Reaction, Macromolecules 47, 1334-1343.
M. C. Chen, Cafferty, B. J., Mamajanov, I., Gállego, I., Khanam, J., Krishnamurthy, R., and Hud, N. V. (2014) Spontaneous prebiotic formation of a β-ribofuranoside that self-assembles with a complementary heterocycle, J. Am. Chem. Soc. 136, 5640-5656.
N. V. Hud, Cafferty, B. J., Krishnamurthy, R., and Williams, L. Dean (2013) The origin of RNA and "My Grandfather's Axe", Chem. Biol. 20, 466-474.
Engelhart, A.E., Hud, N.V. (2010) Primitive Genetic Polymers. Cold Spring Harbor Perspectives in Biology 2, article number a002196.
Horowitz, E.D., Engelhart, A.E., Chen, M.C., Quarles, K.A., Smith, M.W., Lynn, D.G., Hud, N.V. (2010) Intercalation as a means to suppress cyclization and promote polymerization of base-pairing oligonucleotides in a prebiotic world. Proc. Natl. Acad. Sci. USA 107, 5288-5293.
Hud, N.V., Jain, S.S., Li, X., Lynn, D.G. (2007) Addressing the Problems of Base Pairing and Strand Cyclization in Template-Directed Synthesis, Chem. Biodiv. 4, 768-783.
Bean, H.D., Sheng, Y., Collins, J.P., Anet, F.A.L., Leszczynski, J., Hud, N.V. (2007) Formation of a β-Pyrimidine Nucleoside by a Free Pyrimidine Base and Ribose in a Plausible Prebiotic Reaction, J. Am. Chem. Soc. 129, 9556-9557.
N. V. Hud and Anet, F. A., (2000) Intercalation-mediated synthesis and replication: a new approach to the origin of life, J. Theor. Biol. 4, 543-562.