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.
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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.
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).
Patzke, V. & von Kiedrowski, G. Self replicating systems. Arkivoc 2007, 293–310 (2007).
Dadon, Z., Wagner, N. & Ashkenasy, G. The road to non-enzymatic molecular networks. Angew. Chem. Int. Ed. 47, 6128–6136 (2008).
Vidonne, A. & Philp, D. Making molecules make themselves—the chemistry of artificial replicators. Eur. J. Org. Chem. 2009, 593–610 (2009).
Duim, H. & Otto, S. Towards open-ended evolution in self-replicating molecular systems. Beilstein J. Org. Chem. 13, 1189–1203 (2017).
Moreno, A. & Ruiz-Mirazo, K. The problem of the emergence of functional diversity in prebiotic evolution. Biol. Philos. 24, 585–605 (2009).
Kamioka, S., Ajami, D. & Rebek, J. Autocatalysis and organocatalysis with synthetic structures. Proc. Natl Acad. Sci. USA 107, 541–544 (2010).
Higgs, P. G. & Lehman, N. The RNA world: molecular cooperation at the origins of life. Nat. Rev. Genet. 16, 7–17 (2014).
Eschenmoser, A. The search for the chemistry of life’s origin. Tetrahedron 63, 12821–12844 (2007).
Le Vay, K., Weise, L. I., Libicher, K., Mascarenhas, J. & Mutschler, H. Templated self-replication in biomimetic systems. Adv. Biosyst. 3, 1–16 (2019).
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).
Rufo, C. M. et al. Short peptides self-assemble to produce catalytic amyloids. Nat. Chem. 6, 303–309 (2014).
Weingarten, A. S. et al. Self-assembling hydrogel scaffolds for photocatalytic hydrogen production. Nat. Chem. 6, 964–970 (2014).
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).
Omosun, T. O. et al. Catalytic diversity in self-propagating peptide assemblies. Nat. Chem. 9, 805–809 (2017).
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).
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).
Westheimer, F. H. Coincidences, decarboxylation, and electrostatic effects. Tetrahedron 51, 3–20 (1995).
Giger, L. et al. Evolution of a designed retro-aldolase leads to complete active site remodeling. Nat. Chem. Biol. 9, 494–498 (2013).
Lassila, J. K., Baker, D. & Herschlag, D. Origins of catalysis by computationally designed retroaldolase enzymes. Proc. Natl Acad. Sci. USA 107, 4937–4942 (2010).
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).
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).
Hollfelder, F., Kirby, A. J. & Tawfik, D. S. Efficient catalysis of proton transfer by synzymes. J. Am. Chem. Soc. 119, 9578–9579 (1997).
Frederix, P. W. J. M. et al. Structural and spectroscopic properties of assemblies of self-replicating peptide macrocycles. ACS Nano 11, 7858–7868 (2017).
Jiang, L. et al. De novo computational design of retro-aldol enzymes. Science 319, 1387–1391 (2008).
Althoff, E. A. et al. Robust design and optimization of retroaldol enzymes. Protein Sci. 21, 717–726 (2012).
Bjelic, S. et al. Exploration of alternate catalytic mechanisms and optimization strategies for retroaldolase design. J. Mol. Biol. 426, 256–271 (2014).
Capozzi, G. & Modena, G. in The Chemistry of the Thiol Group (ed. Patai, S.) 785–839 (Wiley, 1974).
Dénès, F., Pichowicz, M., Povie, G. & Renaud, P. Thiyl radicals in organic synthesis. Chem. Rev. 114, 2587–2693 (2014).
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).
Carbonell, P., Lecointres, G. & Faulon, J. L. Origins of specificity and promiscuity in metabolic networks. J. Biol. Chem. 286, 43994–44004 (2011).
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).
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).
Nakano, T. & Yade, T. Synthesis, structure, and photophysical and electrochemical properties of a π-stacked polymer. J. Am. Chem. Soc. 125, 15474–15484 (2003).
RStudio Team (RStudio Inc., 2015); https://www.rstudio.com
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).
The authors declare no competing interests.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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.
(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.
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.
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.
UPLC and UV data of the retro-aldol reaction, pH rate profile of the retro-aldol reaction.
UPLC data of the FMOC deprotection reaction.
UPLC and UV data for the kinetic characterization of 1, 13/14 and other replicators. Includes UPLC calibration.
pH titration data.
UPLC data of the emergence experiment with methodol including UPLC calibrations.
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.
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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). https://doi.org/10.1038/s41929-020-0463-8
Nature Communications (2021)
Nature Reviews Chemistry (2020)