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Emergence of light-driven protometabolism on recruitment of a photocatalytic cofactor by a self-replicator

Abstract

Establishing how life can emerge from inanimate matter is among the grand challenges of contemporary science. Chemical systems that capture life’s essential characteristics—replication, metabolism and compartmentalization—offer a route to understanding this momentous process. The synthesis of life, whether based on canonical biomolecules or fully synthetic molecules, requires the functional integration of these three characteristics. Here we show how a system of fully synthetic self-replicating molecules, on recruiting a cofactor, acquires the ability to transform thiols in its environment into disulfide precursors from which the molecules can replicate. The binding of replicator and cofactor enhances the activity of the latter in oxidizing thiols into disulfides through photoredox catalysis and thereby accelerates replication by increasing the availability of the disulfide precursors. This positive feedback marks the emergence of light-driven protometabolism in a system that bears no resemblance to canonical biochemistry and constitutes a major step towards the highly challenging aim of creating a new and completely synthetic form of life.

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Fig. 1: Mechanism of light-driven protometabolic self-replication.
Fig. 2: Optical properties of 2 and 3 on binding to macrocycles derived from 1.
Fig. 3: Replicator 16 enhances photocatalytic oxidation of 1 mediated by 2 and 3.
Fig. 4: Emergence of replicator 16 promotes photocatalytic production of precursors 13/14, which promotes replication.

Data availability

The UPLC data generated and analysed in this Article is included in its Supplementary Information in the form of integrated peak areas and exported traces of representative chromatograms. All other chromatograms are stored locally on their native format and are available on request. All other data generated or analysed during this study are included in this published Article and its Supplementary Information. Source data are provided with this paper.

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Acknowledgements

We thank B. M. Matysiak for performing mass spectrometry measurements. This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement (no. 642192) and was supported by the ERC (AdG 741774), NWO (VICI grant) and the Dutch Ministry of Education, Culture and Science (Gravitation programme 024.001.035). K. L. acknowledges support from Simons Foundation (award no. 553330) and Marie Skłodowska-Curie grant (no. 786350).

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Authors

Contributions

S.O., G.M.S. and K.L. conceived the experiments. G.M.S. performed the experiments related to rose bengal. K.L. performed the experiments related to porphyrins. W.R.B. performed the experiments related to IR luminescence of singlet oxygen. G.M.S, K.L. and S.O. wrote the manuscript.

Corresponding author

Correspondence to Sijbren Otto.

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Authors declare no competing interests.

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Extended data

Extended Data Fig. 1 Absorption spectra of 3 recorded in reduced scattering conditions.

Visible absorption spectra of 3 (10 μM) in buffer (black), and in the presence of 13/14 (1.0 mM in 1; blue) and 16 (1.0 mM in 1; red). In order to show that the increased absorbance of 3 in presence of 16 is not related to scattering, this effect was minimized by recording these spectra in a different spectrophotometer (see Materials), using a wider slit (4 nm), a shorter light path (4.5 mm), and placing the cuvette immediately in front of the detector. Source data

Extended Data Fig. 2 Non-irradiated controls for the emergence of 16 in presence of 2 and 3.

Evolution over time of the concentrations of 1 and 16 in non-irradiated libraries made from 1 and 2 (a) or 1 and 3 (b). The top halves of the graphs show the concentration of 1 (black squares) and 16 (red squares, in units of 1). The bottom halves of the graphs represent the oxidation (black circles) and replication (red circles) rates in the system, calculated by numerical differentiation of the curves in the top halves. Both libraries were prepared exactly as their equivalents in Fig. 4a,b, but they were kept in the dark. Source data

Extended Data Fig. 3 Non-irradiated controls for the emergence of 16 in absence of photosensitizers.

Evolution over time of the concentrations of 1 and 16 in non-irradiated libraries prepared from 1, with no dyes added, in the same conditions as in Fig. 4a (left panel) or Fig. 4b (right panel). The top halves of the graphs show the concentration of 1 (black squares) and 16 (red squares, in units of 1). The bottom halves of the graphs represent the oxidation (black circles) and replication (red circles) rates in the system, calculated by numerical differentiation of the curves in the top halves. Source data

Supplementary information

Supplementary Information

Supplementary Figs. 1–17, Tables 1 and 2.

Supplementary Data

Source Data for Supplementary Figs. 1–11,13–15 and Supplementary Table 2.

Source data

Source Data Fig. 2

Raw spectral data.

Source Data Fig. 3

Integrated peak areas of 1 in chromatograms, and calculation of oxidation rates from them.

Source Data Fig. 4

Integrated peak areas of 1 and 16, and calculation of concentrations and rates from them.

Source Data Extended Data Fig. 1

Raw spectral data.

Source Data Extended Data Fig. 2

Integrated peak areas of 1 and 16, and calculation of concentrations and rates from them.

Source Data Extended Data Fig. 3

Integrated peak areas of 1 and 16, and calculation of concentrations and rates from them.

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Monreal Santiago, G., Liu, K., Browne, W.R. et al. Emergence of light-driven protometabolism on recruitment of a photocatalytic cofactor by a self-replicator. Nat. Chem. 12, 603–607 (2020). https://doi.org/10.1038/s41557-020-0494-4

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