Computational Modeling of RNA Replication in an RNA World

Abstract

The biology of modern life predicts the existence of an ancient RNA world. A phase of evolution in which organisms utilized RNA as a genetic material and a catalyst. However, the existence of an RNA organism necessitates RNA’s ability to self-replicate, which has yet to be proven. In this thesis, we utilize computational modeling to address some of the problems facing RNA replication. In chapter 2, we consider a polymerase ribozyme replicating by the Qβ bacteriophage mechanism. When bound to a surface, limited diffusion allows for survival so long as the termination error rate is below an error threshold. In Chapter 3, we consider the replication of short oligomers through an abiotic mechanism proposed in prebiotic experiments. When limited by substrate availability, competition results in the emergence of uniform RNA polymers from a messy prebiotic soup containing nucleotides of different chirality and sugars. In chapter 4, we consider the possibility of an RNA world lacking cytosine. Without cytosine, the ability of RNA to fold to complex secondary structures is limited. Furthermore, G-U wobble base pairing hinders the transfer of information during replication. Nevertheless, we conclude that an RNA world lacking cytosine may be possible, but more difficult for the initial emergence of life. In chapter 5, we analyze abiotic and viral mechanisms of RNA replication using known kinetic and thermodynamic data. While most mechanisms fail under non-enzymatic conditions, rolling-circle replication appears possible. In chapter 6, we extend our analysis of the rolling-circle mechanism to consider the fidelity of replication. Due to the thermodynamic penalty of incorporating an error, rolling-circle replication appears to undergo error correction. This results in highly accurate replication and circumvents Eigen’s paradox. Rolling-circle replication therefore presents an appealing option for the emergence of RNA replication in an RNA world.