UC San Diego

Throughout human history, the nature of life’s origin has been a prominent question seen with much philosophical importance. Our best scientific model for the origin of life is the RNA world hypothesis, which describes the earliest forms of life as having RNA as the only genome and the only genome-encoded catalysts, as opposed to the DNA-RNA-protein world of modern biology. Research into geology and prebiotic chemistry, however, describe a complex chemical environment in which the ribozymes would have had many catalytic possibilities to explore. In this dissertation, I present the results of two in vitro selections which examined the utility of peptides and lanthanides as cofactors for triphosphorylation ribozymes. These ribozymes utilize trimetaphosphate, a prebiotically plausible polyphosphate source, to triphosphorylate their own 5’-ends as a simpler analog for studying nucleoside activation. The first selection was done in the presence of ten octapeptides of varying prebiotic plausibility, and two ribozymes were examined in detail. Ribozyme 20 displayed a strongly beneficial relationship with one specific peptide, which increased the RNA’s activity by 900 (+/- 300)-fold, providing an example of a ribozyme that could benefit from a primitive translation system. In contrast, the mild (2-10 fold) benefit for ribozyme 23 interacting with six of the ten peptides provides an example of a ribozyme that could possibly benefit from random, abiotically assembled peptides. The other selection, using ytterbium as a metal ion cofactor instead of the standard magnesium, yielded many active sequences. One sequence, ribozyme 51, was studied in detail and was very sensitive to the ionic radius of the lanthanide. It required a lanthanide for activity and seemed to only be able to bind trimetaphosphate as a complex with the lanthanide, but still seemed to prefer other metal cations for folding. These results provide insight into the relationships of peptides and lanthanides with the development of catalytic RNAs, as well as opening doors for future study for understanding both the origin of life and the general principles of their interactions.