Peptide-Assisted Nonenzymatic RNA Replication in Coacervate Droplets

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Peptide-Assisted Nonenzymatic RNA Replication in Coacervate Droplets

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Title: Peptide-Assisted Nonenzymatic RNA Replication in Coacervate Droplets
Author: Jia, Tony Z.
Citation: Jia, Tony Z. 2016. Peptide-Assisted Nonenzymatic RNA Replication in Coacervate Droplets. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences.
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Abstract: Life on earth may have first appeared in the form of a protocell capable of metabolism and containing a self-replicating informational polymer. This polymer was likely to have been RNA due to its ability to serve both as an informational and a catalytic biomolecule in modern life, spawning the “RNA world” hypothesis and suggesting that RNA could have facilitated its own replication without the aid of polymerases. Nonenzymatic replication of RNA was a critical process required for the assembly of the first ribozyme, an essential component for sustained Darwinian evolution. However, template-directed copying of RNA results in a double-stranded product; following strand separation, rapid strand reannealing outcompetes slow nonenzymatic template copying, rendering multiple rounds of RNA replication impossible.

The lack of a prebiotically plausible route to an RNA polymerase ribozyme raises questions about a purely RNA world, prompting some to propose a peptide-RNA world wherein peptides and RNA emerged simultaneously and complementarily. Considerable evidence supports the possibility that peptides and RNA were present together on the primitive earth. Arginine-rich peptides are particularly interesting as they can bind strongly to RNA and form coacervate droplets. These droplets can segregate and concentrate biopolymers and can even enhance catalytic activity, leading some to speculate that the earliest protocells may have been membrane-free phase-separated entities similar to coacervate or aqueous two-phase system (ATPS) droplets.

We first introduce the processes by which amino acids and peptides could have formed on the abiotic earth and also highlight some prebiotically important features of coacervate droplets. We challenge the broad notion that all peptide-based coacervate droplets should be used as membrane-free protocell models moving forward. We next determine that RNA strands within ATPS and ATP/poly-L-lysine coacervate droplets rapidly exchange with the surrounding aqueous phase, providing once specific example of a coacervate droplet system that is not a suitable membrane-free protocell models. We then show that the annealing of complementary RNA strands is slowed by several orders of magnitude within oligoarginine/RNA coacervate droplets. However, we also observe that primer-template binding and template-directed primer extension can still proceed within these droplets even in the presence of inhibitory strands, providing a pathway by which RNA on the early earth could have replicated and evolved efficiently. This strategy for enabling further rounds of replication suggests one mechanism by which short, non-coded peptides could have enhanced early cellular fitness, potentially explaining how longer, coded peptides, i.e. proteins, came to prominence in modern biology.
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