Ribozyme activity modulates the physical properties of RNA–peptide coacervates

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    Experimental models of simple cell-like compartments can help us to understand how biology operated early in its history. The authors convincingly show how the properties of coacervate droplets can be influenced by the activity of ribozymes inside them. This important result potentially provides a new route for biologists or chemists to establish cell mimics that support the evolution of biomolecules within.

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Abstract

Condensed coacervate phases are now understood to be important features of modern cell biology, as well as valuable protocellular models in origin-of-life studies and synthetic biology. In each of these fields, the development of model systems with varied and tuneable material properties is of great importance for replicating properties of life. Here, we develop a ligase ribozyme system capable of concatenating short RNA fragments into long chains. Our results show that the formation of coacervate microdroplets with the ligase ribozyme and poly(L-lysine) enhances ribozyme rate and yield, which in turn increases the length of the anionic polymer component of the system and imparts specific physical properties to the droplets. Droplets containing active ribozyme sequences resist growth, do not wet or spread on unpassivated surfaces, and exhibit reduced transfer of RNA between droplets when compared to controls containing inactive sequences. These altered behaviours, which stem from RNA sequence and catalytic activity, constitute a specific phenotype and potential fitness advantage, opening the door to selection and evolution experiments based on a genotype–phenotype linkage.

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  1. eLife assessment

    Experimental models of simple cell-like compartments can help us to understand how biology operated early in its history. The authors convincingly show how the properties of coacervate droplets can be influenced by the activity of ribozymes inside them. This important result potentially provides a new route for biologists or chemists to establish cell mimics that support the evolution of biomolecules within.

  2. Reviewer #1 (Public Review):

    RNA-based self-replication systems might have been concentrated and compartmentalized with peptides by forming droplet-like complexes before the emergence of cellular organisms enveloped by lipid membranes. This report clearly shows that the physical properties of such droplets (phenotypes) can be affected by the activities of a ligase ribozyme in the droplets. This suggests that sequences of such ribozymes (genotypes) might have been selected not only for their direct activities (e.g., elongation of RNA) but also for their indirect effects on the droplet phenotypes (e.g., more viscous/solid droplets formed by the elongated RNAs) on the ancient earth. However, the exact requirements (e.g., average/maximum length of the ligated RNAs + double strand formation) for such phenotypic changes are not assessed in …

  3. Reviewer #2 (Public Review):

    To understand the origins of life, it is often necessary to establish synthetic molecular systems that model how primitive cells might have operated. Adopting this approach, here Le Vay et al. tackle one of the mysteries of early cells: how could primitive biomolecules have controlled the behavior of the compartments they inhabited? By forming coacervate droplets from polylysine peptides and ribozymes (catalytic RNAs), they observe changes in droplet properties driven by ribozyme activity and propose a route to form an integrated protocellular system that allows the evolution of biomolecules based on compartment behavior, modeling potential early life processes.

    Polymers of opposite charge can phase-separate into coacervate droplets in equilibrium with surrounding aqueous phases. Such condensates are thought …

  4. Reviewer #3 (Public Review):

    The study investigates the consequences of mixing a ligase ribozyme, its substrates, and oligo(Lys) peptides of different lengths in the context of a coacervate droplet protocell in a 'Nucleic Acid World' as an early stage of life. The study shows convincingly several very interesting results that are certain to have an impact on origins-of-life studies: First, the activity of ribozymes in the coacervate droplets - the formation of longer RNAs - affects the size of the droplets, with inactive ribozymes leading to more droplet fusion. Second, this behavior is reflected in the adhesion to hydrophobic surfaces, showing that not only the size but also the physical properties of the droplets are changed by ribozyme catalysis. Third, the exchange rate of material between droplets is also affected by ribozyme …