Theoretical Analysis of Nonenzymatic RNA Replication within the Virtual Circular Genome Scenario

The transition from prebiotic chemistry to living systems requires the emergence of a reliable enzyme-free replication mechanism. Despite recent advances in template-directed polymerization, challenges like the short length of copied products and high error rates persist. In this work, we analyze a recently proposed prebiotic replication scenario, the so-called Virtual Circular Genome (VCG) [Zhou et al., RNA 27, 1-11 (2021)]: Replication takes place in a pool of oligomers, where each oligomer contains a subsequence of a circular genome, such that the oligomers encode the full genome collectively. While the sequence of the circular genome may be reconstructed based on long oligomers, short oligomers merely act as replication feedstock. We observe a competition between the predominantly error-free ligation of a short oligomer to a long oligomer and the predominantly erroneous ligation of two long oligomers. Increasing the length of long oligomers and reducing their concentration decreases the fraction of erroneous ligations, enabling high-fidelity replication in the VCG. Alternatively, the problem of erroneous products can be mitigated if only monomers are activated, such that each ligation involves at least one monomer. Surprisingly, in such systems, shorter oligomers are extended by monomers more quickly than long oligomers, a phenomenon which has already been observed experimentally [Ding et al., JACS 145, 7504-7515 (2023)]. Our work provides a theoretical explanation for this behavior, and predicts its dependence on system parameters such as the concentration of long oligomers.