Hydrophobic-cationic peptides enhance RNA polymerase ribozyme activity by accretion

Peiying Li, Philipp Holliger, Shunsuke Tagami

Preprint posted on 23 February 2021

Article now published in Nature Communications at

Accretion in the prebiotic world: simple peptides might pave the way to understanding the history of biological life

Selected by Utrecht Protein Folding and Assembly

Categories: biochemistry

Written by: Julia van den Boogert, Isabel van Rongen, Emile van Weert & Olivier Zadelhoff


The origin of life is thought to have arisen from an RNA world in which ribozymes catalysed biochemical reactions and RNA stored genetic information. However, the emergence of RNA-based life required compartmentalization, or otherwise RNA replication systems would be overrun and genetic selection could not have occurred. Compartmentalization may have been achieved by accretion of peptides and RNA. The term accretion implies that biopolymers gradually accumulate into macromolecular aggregates stabilized by intermolecular forces. Accretion of peptides and RNA could lead to an increased local concentration and a basic form of compartmentalization, which may have played a role in the origin of life. However, the impact of accretion on ribozymes is largely unknown.

Examining the accretion hypothesis, Li et al. discover the RNA binding peptide P43 (AKKVWIIMGGS), which is able to accrete multiple ribozyme species and regulate their activity.


Key findings

The authors obtain P43 by performing a randomized peptide phage display, selecting for peptides that bind and regulate RNA polymerase ribozyme (RPR). P43 is a cationic-hydrophobic peptide which forms insoluble aggregates that can accrete RNA and ribozymes on its surface. The phage display reveals that P43 inhibits RPR activity. By assessing the inhibiting potential of truncated P43 variants, the authors find that not only hydrophobic but also cationic residues are crucial in forming P43 aggregates and in accretion, indicating a role for electrostatic interactions between cationic residues and anionic RNA. This differs from a previously studied, purely cationic, non-aggregating (Lys)10 prebiotic peptide (Tagami et al., 2017).

P43 shows preferential binding for longer RNA strands, hence acting as a suitable platform for the formation of longer biopolymers. By showing that the shorter and simpler peptide (Lys2)(Val)6 is also able to inhibit RPR activity, the authors prove that the P43 inhibitory efficacy is a general feature of cationic-hydrophobic peptides. This simplification is a proof of concept, making the accretion model even more plausible in evolutionary terms.

The prebiotic hypothesis posits that salt concentrations frequently fluctuated. Because of this, the authors are curious about the influence of salt concentration on the P43-RPR interaction. Low salt allows P43 aggregates to inhibit RPR, likely because the electrostatic interactions with RNA are so tight that they distort the ribozyme structure. At high salt concentrations, loosened interactions between accreted RNA and P43 enhance RPR activity. Next, the authors demonstrate that P43 captures inactive ribozymes at low salt, and reactivates them by subsequent resuspension in high salt concentrations.

These findings suggest a potential role for freeze/thaw cycles in the prebiotic world. Diurnal cycling of wet and dry periods brought about the occurrence of three conditions: dry, wet and condensed. The dry phases would have favored biopolymer formation due to dehydration; subsequent wet conditions the accretion of biomaterials through the influx of water. Entering condensed conditions through evaporation of water, the enhancement of ribozyme activity by peptide aggregates would have occurred, as salt concentrations increased (Figure 6). In short, it is likely that freeze/thaw cycles in combination with cationic/hydrophobic peptides like P43 enabled RNA polymerization without the use of complicated biochemical pathways.

Figure 6 from the preprint. Schematic representation displaying potential role of freeze/thaw cycling in prebiotic peptide synthesis. Reproduced with permission from the authors.


The authors of this preprint advocate the importance of accretion in the formation of prebiotic peptides. As accretion leads to a gradual increase in RNA and peptide concentration, it might have preceded the formation of liquid-like compartments. Ultimately, compartmentalization through accretion protects from environmental stress factors, thereby enabling the retainment of novel functions. Consequently, bulk P43-like peptide synthesis would pose evolutionary advantages even before the emergence of cell-like life.


What we like about this preprint

Compartmentalization is crucial for the origin of life, however there is no consensus as to how this was attained. It is interesting to see how the authors describe and demonstrate that compartmentalization can be achieved through accretion. We like the simplicity of the accretion model as one of the first steps towards the immensely complex emergence of life. We believe that this paper is an extension to our knowledge on the origin of life and can perhaps grant insights in other fields of biochemical research.



  • Attwater, J., Wochner, A., & Holliger, P. (2013). In-ice evolution of RNA polymerase ribozyme activity. Nature chemistry, 5(12), 1011–1018.
  • Tagami, S., Attwater, J., & Holliger, P. (2017). Simple peptides derived from the ribosomal core potentiate RNA polymerase ribozyme function. Nature chemistry, 9(4), 325–332.2

Tags: accretion, origin of life, prebiotic chemistry, ribozymes

Posted on: 23 April 2021

doi: Pending

Read preprint (2 votes)

Questions and author's response

Shunsuke Tagami shared

1. Arginine residues bind stronger to RNA than lysine residues. Did the phage display include RR sequenced peptides that also had an inhibitory effect on RPR? In a similar fashion, did you consider testing R2V6 for inhibitory effects on RPR?

We did not find peptide containing RR in phage display but we have tested R10 in our previous report (Nat Chem. 2017). While K10 stimulated the activity of RPR, R10 strongly inhibited it probably because R10 binds the ribozyme too tight. However, we are still not sure how strong (or weak) the interactions between RNA and peptides should be to have an inhibitory (or stimulative) effect. It would be interesting to test a series of peptides having different numbers of K, R, and V residues.

2. A previous study (Attwater et al., 2013) did a similar experiment in which a different ribozyme (R18 RNA polymerase) had low activity at high Mg2+conditions (200 mM). In contrast, you find enhanced RPR activity at high Mg2+concentrations. Which characteristics of RNA polymerase ribozymes are related to salt conditions and its activity?

RNA polymerase ribozymes are generally more active at higher Mg2+ but RNA degrade quickly in such conditions. To overcome this problem, we use freezing conditions (Attwater et al., 2013) or peptide co-factors (Tagami et al., 2017).

3. The experiments examining P43 and RNA interactions were done without possible contaminants. In a prebiotic environment there would have been other types of peptides than P43. Do you think other types of peptides could interfere with the accretion of P43 and RNA?

This is a really interesting question. We need to test it experimentally. Contamination of other peptides might interfere with the stimulative interactions between RPR and P43 but there might also be peptide cocktails that work in a better way than simply adding P43. We think some peptides might also have been selected by accretion from such a mixture of peptides.

Phil Holliger comments:

On 3) agree really fascinating question. Clearly some form of fractionation could go on but importantly Shunsuke’s work has shown that binding and activation are not the same.  An even more tricky problem: assuming a peptide is really useful to the RNA replicase, how does the system find a way to make heritable?

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