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bioRxiv · 10.1101/2024.07.17.603910

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

Burger, L.·Gerland, U.
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Abstract

The transition from prebiotic chemistry to living systems requires the emergence of a scheme for enzyme-free genetic replication. Here, 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, monomers and short oligomers merely act as replication feedstock. We observe a competition between the predominantly error-free ligation of a feedstock molecule 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 formation of erroneous products can be suppressed if each ligation involves at least one monomer, while ligations between two long oligomers are effectively prevented. This kinetic discrimination (favoring monomer incorporation over oligomer-oligomer ligation) may be an intrinsic property of the activation chemistry, or can be externally imposed by selectively activating only monomers in the pool. Surprisingly, under these conditions, 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. Taken together, the VCG constitutes a promising scenario of prebiotic information replication: It could mitigate challenges of in non-enzymatic copying via template-directed polymerization, such as short lengths of copied products and high error rates.

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Burger, L., Gerland, U.. 2024-07-19. Theoretical Analysis of Nonenzymatic RNA Replication within the Virtual Circular Genome Scenario. https://doi.org/10.1101/2024.07.17.603910

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