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Harnessing chemical energy for the activation and joining of prebiotic building blocks

A Publisher Correction to this article was published on 18 November 2020

This article has been updated


Life is an out-of-equilibrium system sustained by a continuous supply of energy. In extant biology, the generation of the primary energy currency, adenosine 5′-triphosphate and its use in the synthesis of biomolecules require enzymes. Before their emergence, alternative energy sources, perhaps assisted by simple catalysts, must have mediated the activation of carboxylates and phosphates for condensation reactions. Here, we show that the chemical energy inherent to isonitriles can be harnessed to activate nucleoside phosphates and carboxylic acids through catalysis by acid and 4,5-dicyanoimidazole under mild aqueous conditions. Simultaneous activation of carboxylates and phosphates provides multiple pathways for the generation of reactive intermediates, including mixed carboxylic acid–phosphoric acid anhydrides, for the synthesis of peptidyl–RNAs, peptides, RNA oligomers and primordial phospholipids. Our results indicate that unified prebiotic activation chemistry could have enabled the joining of building blocks in aqueous solution from a common pool and enabled the progression of a system towards higher complexity, foreshadowing today’s encapsulated peptide–nucleic acid system.

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Fig. 1: Joining of prebiotic building blocks driven by common activation chemistry in aqueous solution.
Fig. 2: Proposed reaction scheme of the activation chemistry.

Data availability

All data generated or analysed during this study are included in the manuscript and the Supplementary Information.

Change history

  • 18 November 2020

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.


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This research was supported by the Medical Research Council (no. MC_UP_A024_1009 to J.D.S.) and the Simons Foundation (no. 290362 to J.D.S.). We thank all J.D.S. group members for fruitful discussions. We thank R. Pascal for helpful suggestions.

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Authors and Affiliations



Z.L., L.-F.W., J.X., C.B. and D.A.R. carried out the experiments under the supervision of J.D.S. All authors wrote the manuscript. All authors discussed the results and commented on the manuscript.

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Correspondence to John D. Sutherland.

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Supplementary Information

Supplementary Figs. 1–68 and Tables 1–3.

Supplementary Data

Statistical Source Data for Supplementary Figs. 5, 9, 10, 32, 37 and 65.

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Liu, Z., Wu, LF., Xu, J. et al. Harnessing chemical energy for the activation and joining of prebiotic building blocks. Nat. Chem. 12, 1023–1028 (2020).

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