Experimental investigations of informational complexity and RNA functional activity

At the level of individual biopolymers understanding how information, structure and function are related is a matter of chemistry and physics. By studying sets of synthetic structures we can develop quantitative ideas about the principles that dictate the mapping between biopolymer sequence, structure, and function spaces; ultimately, this will shed light on the origins and early evolution of life (Chapter 1).; Informational measures quantify the fraction of all possible states that are meaningful in a certain system and environment. In Chapter 2 we show that the informational cost to improve activity in a set of in vitro-selected RNA aptamers that bind GTP with affinities spanning almost three orders of magnitude is roughly equivalent to specifying 5 additional conserved positions in an RNA structure. Surprisingly, two ribozymes that catalyze RNA-RNA ligation reactions exhibit the same information-activity cost, hinting that there may be a general information-activity relationship.; In Chapter 3 we sought a physical mechanism to explain the association between information and activity. Extensive analog binding studies demonstrate that aptamers selected for higher-affinity binding do not interact more specifically with GTP. These results suggest that the informational cost to improve activity reflects the difficulty of increasing the number of interactions within the RNA structures themselves, as opposed to the difficulty of making more contacts with the ligand.; The 3D solution NMR structure of the Class I GTP aptamer (Chapter 4) further supports a model where increasing the number of intra-RNA contacts is the simplest way to improve activity. Interestingly, the Class I GTP aptamer achieves a Kd that is 80 fold better than the Sassanfar ATP aptamer Kd even though they bind their ligands in a qualitatively similar manner. The informationally-complex Class I GTP aptamer has a network of stabilizing interactions that the Sassanfar ATP aptamer lacks. We conclude that these stabilizing elements are responsible for the difference in binding affinities. We speculate that the informational cost to improve RNA stability (and thus function) could be broadly applicable---leading to a general correspondence between informational complexity and RNA functional activity.