Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Chance emergence of catalytic activity and promiscuity in a self-replicator


How life can emerge from inanimate matter is one of the grand questions in science. Self-replicating molecules are necessary for the transition from chemistry to biology, but they need to acquire additional functions for life to emerge. Catalysis is one of the most essential of such functionalities, but mechanisms through which self-replicators can acquire catalytic and, in extension, metabolic properties have remained elusive. Here we show how catalytic activity and promiscuity in a self-replicator emerges through co-option: features that are selected to benefit replication inadvertently result in an arrangement of chemical functionalities that is conducive to catalysis. Specifically, we report self-assembly driven self-replicators that promote both a model retro-aldol reaction and the cleavage of fluorenylmethoxycarbonyl groups, with the latter transformation exerting a positive feedback on replication (protometabolism). Such chance invention of new function at the molecular level marks a pivotal step toward the de novo synthesis of life.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1: Fibre formation from building block 1 creates microenvironments that are conducive to catalysis.
Fig. 2: The catalytic activity of 16 in a model retro-aldol reaction emerges due to the combination of a substrate-binding pocket and nucleophilic lysine residues.
Fig. 3: The emergence of a protometabolism in response to the cleavage of FMOC-glycine by replicator fibres.

Data availability

Data for Figs. 2 and 3 and Extended Data Figs. 1–3 and 5 are available as source data with this paper. All other data are available from the corresponding author on request.


  1. Ruiz-Mirazo, K., Briones, C. & de la Escosura, A. Prebiotic systems chemistry: new perspectives for the origins of life. Chem. Rev. 114, 285–366 (2014).

    Article  CAS  Google Scholar 

  2. Patzke, V. & von Kiedrowski, G. Self replicating systems. Arkivoc 2007, 293–310 (2007).

    Article  Google Scholar 

  3. Dadon, Z., Wagner, N. & Ashkenasy, G. The road to non-enzymatic molecular networks. Angew. Chem. Int. Ed. 47, 6128–6136 (2008).

    Article  CAS  Google Scholar 

  4. Vidonne, A. & Philp, D. Making molecules make themselves—the chemistry of artificial replicators. Eur. J. Org. Chem. 2009, 593–610 (2009).

    Article  Google Scholar 

  5. Duim, H. & Otto, S. Towards open-ended evolution in self-replicating molecular systems. Beilstein J. Org. Chem. 13, 1189–1203 (2017).

    Article  CAS  Google Scholar 

  6. Moreno, A. & Ruiz-Mirazo, K. The problem of the emergence of functional diversity in prebiotic evolution. Biol. Philos. 24, 585–605 (2009).

    Article  Google Scholar 

  7. Kamioka, S., Ajami, D. & Rebek, J. Autocatalysis and organocatalysis with synthetic structures. Proc. Natl Acad. Sci. USA 107, 541–544 (2010).

    Article  CAS  Google Scholar 

  8. Higgs, P. G. & Lehman, N. The RNA world: molecular cooperation at the origins of life. Nat. Rev. Genet. 16, 7–17 (2014).

    Article  Google Scholar 

  9. Eschenmoser, A. The search for the chemistry of life’s origin. Tetrahedron 63, 12821–12844 (2007).

    Article  CAS  Google Scholar 

  10. Le Vay, K., Weise, L. I., Libicher, K., Mascarenhas, J. & Mutschler, H. Templated self-replication in biomimetic systems. Adv. Biosyst. 3, 1–16 (2019).

    Google Scholar 

  11. Müller, M. M., Windsor, M. A., Pomerantz, W. C., Gellman, S. H. & Hilvert, D. A rationally designed aldolase foldamer. Angew. Chem. Int. Ed. 48, 922–925 (2009).

    Article  Google Scholar 

  12. Rufo, C. M. et al. Short peptides self-assemble to produce catalytic amyloids. Nat. Chem. 6, 303–309 (2014).

    Article  CAS  Google Scholar 

  13. Weingarten, A. S. et al. Self-assembling hydrogel scaffolds for photocatalytic hydrogen production. Nat. Chem. 6, 964–970 (2014).

    Article  CAS  Google Scholar 

  14. Tena-Solsona, M. et al. Emergent catalytic behavior of self-assembled low molecular weight peptide-based aggregates and hydrogels. Chem. A Eur. J. 22, 6687–6694 (2016).

    Article  CAS  Google Scholar 

  15. Omosun, T. O. et al. Catalytic diversity in self-propagating peptide assemblies. Nat. Chem. 9, 805–809 (2017).

    Article  CAS  Google Scholar 

  16. Malakoutikhah, M. et al. Uncovering the selection criteria for the emergence of multi-building-block replicators from dynamic combinatorial libraries. J. Am. Chem. Soc. 135, 18406–18417 (2013).

    Article  CAS  Google Scholar 

  17. Colomb-Delsuc, M., Mattia, E., Sadownik, J. W. & Otto, S. Exponential self-replication enabled through a fibre elongation/breakage mechanism. Nat. Commun. 6, 7427 (2015).

    Article  CAS  Google Scholar 

  18. Westheimer, F. H. Coincidences, decarboxylation, and electrostatic effects. Tetrahedron 51, 3–20 (1995).

    Article  CAS  Google Scholar 

  19. Giger, L. et al. Evolution of a designed retro-aldolase leads to complete active site remodeling. Nat. Chem. Biol. 9, 494–498 (2013).

    Article  CAS  Google Scholar 

  20. Lassila, J. K., Baker, D. & Herschlag, D. Origins of catalysis by computationally designed retroaldolase enzymes. Proc. Natl Acad. Sci. USA 107, 4937–4942 (2010).

    Article  CAS  Google Scholar 

  21. Tanaka, F., Fuller, R., Shim, H., Lerner, R. A. & Barbas, C. F. Evolution of aldolase antibodies in vitro: correlation of catalytic activity and reaction-based selection. J. Mol. Biol. 335, 1007–1018 (2004).

    Article  CAS  Google Scholar 

  22. Suh, J., Scarpa, I. S. & Klotz, I. M. Catalysis of decarboxylation of nitrobenzisoxazolecarboxylic acid and of cyanophenylacetic acid by modified polyethylenimines. J. Am. Chem. Soc. 98, 7060–7064 (1976).

    Article  CAS  Google Scholar 

  23. Hollfelder, F., Kirby, A. J. & Tawfik, D. S. Efficient catalysis of proton transfer by synzymes. J. Am. Chem. Soc. 119, 9578–9579 (1997).

    Article  CAS  Google Scholar 

  24. Frederix, P. W. J. M. et al. Structural and spectroscopic properties of assemblies of self-replicating peptide macrocycles. ACS Nano 11, 7858–7868 (2017).

    Article  CAS  Google Scholar 

  25. Jiang, L. et al. De novo computational design of retro-aldol enzymes. Science 319, 1387–1391 (2008).

    Article  CAS  Google Scholar 

  26. Althoff, E. A. et al. Robust design and optimization of retroaldol enzymes. Protein Sci. 21, 717–726 (2012).

    Article  CAS  Google Scholar 

  27. Bjelic, S. et al. Exploration of alternate catalytic mechanisms and optimization strategies for retroaldolase design. J. Mol. Biol. 426, 256–271 (2014).

    Article  CAS  Google Scholar 

  28. Capozzi, G. & Modena, G. in The Chemistry of the Thiol Group (ed. Patai, S.) 785–839 (Wiley, 1974).

  29. Dénès, F., Pichowicz, M., Povie, G. & Renaud, P. Thiyl radicals in organic synthesis. Chem. Rev. 114, 2587–2693 (2014).

    Article  Google Scholar 

  30. Leveson-Gower, R. B., Mayer, C. & Roelfes, G. The importance of catalytic promiscuity for enzyme design and evolution. Nat. Rev. Chem. 3, 687–705 (2019).

    Article  CAS  Google Scholar 

  31. Carbonell, P., Lecointres, G. & Faulon, J. L. Origins of specificity and promiscuity in metabolic networks. J. Biol. Chem. 286, 43994–44004 (2011).

    Article  CAS  Google Scholar 

  32. Czárán, T., Könnyu, B. & Szathmáry, E. Metabolically coupled replicator systems: overview of an RNA-world model concept of prebiotic evolution on mineral surfaces. J. Theor. Biol. 381, 39–54 (2015).

    Article  Google Scholar 

  33. Guo, H. & Tanaka, F. A fluorogenic aldehyde bearing a 1,2,3-triazole moiety for monitoring the progress of aldol reactions. J. Org. Chem. 74, 2417–2424 (2009).

    Article  CAS  Google Scholar 

  34. Nakano, T. & Yade, T. Synthesis, structure, and photophysical and electrochemical properties of a π-stacked polymer. J. Am. Chem. Soc. 125, 15474–15484 (2003).

    Article  CAS  Google Scholar 

  35. RStudio Team (RStudio Inc., 2015);

Download references


We gratefully acknowledge a Marie Skłodowska Curie Individual Fellowship (project no. 751509) to C.M. and funding from the Netherlands Organisation for Scientific Research (NWO, Veni grant no. 722.017.007 to C.M., Vici grant no. 724.012.002 to S.O.), as well as support from the ERC, COST (CM1304) and the Dutch Ministry of Education, Culture and Science (Gravitation programme 024.001.035).

Author information

Authors and Affiliations



C.M and S.O. supervised the overall project. J.O. conceived, designed and performed the experiments related to the retro-aldol reaction. A.S.H. conceived, designed and performed the experiments relating to the FMOC-glycine cleavage reaction. J.O, A.S.H, C.M. and S.O. co-wrote the paper. All authors discussed the results and commented on the manuscript.

Corresponding authors

Correspondence to Clemens Mayer or Sijbren Otto.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Extended Data Fig. 1 Kinetic characterization of 1, 13/14 and replicators.

Comparison of the reaction progress between the uncatalyzed retro-aldol reaction (red in a and b) and that in the presence of different concentration of 1 (a) and varying concentrations of a mixture of 13/14 (b). (c): Reaction progress monitored spectrophotometrically with 16 (25 μM) and methodol (600 μM, in triplicates with single standard deviation shown as shaded area). Red and blue dotted lines are linear fits for the observed burst (first 20 minutes) and steady state rate (100–200 minutes). (d): Apparent catalytic efficiencies for the cleavage of methodol (200 μM) of 16 and replicators featuring lysine-to-arginine mutations.

Source data

Extended Data Fig. 2 pH titration and TEM studies of 16 replicators.

(a) pH titration for 1 and 16 fibres in water (both in duplicates). The buffering capacity of monomers at a pH between 5 and 7 can be attributed to the presence of aromatic thiols in 1. In contrast, 16 fibres do not reveal appreciable levels of an ionizable group in the range from 5–8. The absence of a recognisable plateau at the apparent pKa of the lysines active in the retro-aldol (pKa,app = 7.4; Fig. 2e) or FMOC-glycine cleavage reactions (pKa,app = 7.1; Extended data Fig. 5a) indicates that, for each of these reactions, the fraction of lysine residues in the fibres that are catalytically active is low. All error bars shown correspond to a single standard deviation. (b-c) TEM images of 16 fibres at low and high pH regimes do not show a change in morphology.

Source data

Extended Data Fig. 3 Emergence of catalytic activity of the retro-aldol reaction in a stirred sample of 1 correlates with fibre formation.

(a): Rate of formation of retro-aldol product 3 over the course of the experiments. Solid line represents a linear fit to the uncatalyzed reaction. (b–d): Concentration of 16 (b), 1 (c), and 14 (d) followed over time. Colour code as indicated in the legend.

Source data

Extended Data Fig. 4 Time-dependent TEM experiments.

For agitated samples (a–f) fibres become detectable after 8.5 hours, which correlates with the increase in the concentration of 16 in the experiment shown in Fig. 2. Neither the non-agitated sample (g, h) nor the sample lacking 1 (i) showed detectable levels of fibres after 48 hours.

Extended Data Fig. 5 Emergence of catalytic activity of FMOC cleavage in a stirred sample of 1 correlates with fibre formation and an increase in the oxidation rate.

(a), pH rate profile for the cleavage of FMOC-glycine (100 μM) catalysed by replicator 16 (40 μM in 1). (b), Apparent catalytic efficiencies for the cleavage of FMOC glycine (200 μM) by 16 and replicators featuring lysine-to-arginine mutations. (c), Data for experiments as shown in Fig. 3b, but using 200 μM FMOC-glycine. The emergence of 16 (dark blue circles) coincides with the onset of FMOC-glycine cleavage (red circles) and 16 replicates faster when compared to a sample that does not contain FMOC-glycine (light blue circles). (d), A comparison of oxidation rates in the same experiment showed an up to 4.7 fold increase (purple arrow) once 5 is liberated, providing further evidence for the positive feedback loop shown in Fig. 3b. (e), A comparison of the oxidation of 1 (100 μM) in presence (red circles) and absence (blue circles) of 5 (100 μM) confirmed that this FMOC-cleavage product is responsible for enhancing the rate of oxidation of 1. Experiments were performed in borate buffer pH 8.1, containing 5% acetonitrile at 40 °C. All error bars shown correspond to a single standard deviation.

Source data

Supplementary information

Supplementary Information

Supplementary Discussion, Figs. 1–6 and Tables 1 and 2.

Source data

Source Data Fig. 2

UPLC and UV data of the retro-aldol reaction, pH rate profile of the retro-aldol reaction.

Source Data Fig. 3

UPLC data of the FMOC deprotection reaction.

Source Data Extended Data Fig. 1

UPLC and UV data for the kinetic characterization of 1, 13/14 and other replicators. Includes UPLC calibration.

Source Data Extended Data Fig. 2

pH titration data.

Source Data Extended Data Fig. 3

UPLC data of the emergence experiment with methodol including UPLC calibrations.

Source Data Extended Data Fig. 5

pH rate profile for the cleavage of FMOC-glycine, catalytic efficiencies of various replicators towards FMOC-glycine cleavage, UPLC data for emergence experiments with FMOC-glycine and measurements of oxidation of building block 1 with and without DBF. Also includes UPLC calibration and the determination of the extinction coefficient.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Ottelé, J., Hussain, A.S., Mayer, C. et al. Chance emergence of catalytic activity and promiscuity in a self-replicator. Nat Catal 3, 547–553 (2020).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing