Abstract
The single chirality of biological molecules is a signature of life. Yet, rationalizing how single chirality emerged remains a challenging goal1. Research has commonly focused on initial symmetry breaking and subsequent enantioenrichment of monomer building blocks—sugars and amino acids—that compose the genetic polymers RNA and DNA as well as peptides. If these building blocks are only partially enantioenriched, however, stalling of chain growth may occur, whimsically termed in the case of nucleic acids as “the problem of original syn”2. Here, in studying a new prebiotically plausible route to proteinogenic peptides3,4,5, we discovered that the reaction favours heterochiral ligation (that is, the ligation of l monomers with d monomers). Although this finding seems problematic for the prebiotic emergence of homochiral l-peptides, we demonstrate, paradoxically, that this heterochiral preference provides a mechanism for enantioenrichment in homochiral chains. Symmetry breaking, chiral amplification and chirality transfer processes occur for all reactants and products in multicomponent competitive reactions even when only one of the molecules in the complex mixture exhibits an imbalance in enantiomer concentrations (non-racemic). Solubility considerations rationalize further chemical purification and enhanced chiral amplification. Experimental data and kinetic modelling support this prebiotically plausible mechanism for the emergence of homochiral biological polymers.
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Data availability
All source data are available in the Supplementary Information, including a video of the 3D plot in Fig. 1c. CoPaSi modelling files are available from the authors upon request. Crystallographic data for structures have been deposited at the Cambridge Crystallographic Data Centre, with numbers 2237664 (ld-dl) and 2238268 (ll-dd).
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Acknowledgements
D.G.B. acknowledges funding from the Simons Foundation under the Simons Collaboration on the Origins of Life (SCOL 287625) and the John C. Martin Endowed Chair in Chemistry. We acknowledge Y. Zhou for help in producing the 3D plot in Fig. 1c; L. Pasternack of the Scripps NMR facility for help with quantitative 13C-NMR experiments; the Scripps Automated Synthesis Facility, including for development of chiral assays; and M. Gembicky and J. Bailey for completing the crystallographic work at the X-ray Crystallography Facility at the University of California, San Diego.
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D.G.B. conceived the project, verified kinetic modelling, constructed the figures and wrote the first draft of the manuscript. M.D. carried out all experimental work (including developing 13C-NMR methodology for chiral analyses of complex product mixtures), developed the chiral amplification model and carried out kinetic modelling. J.Y. aided with critical chiral analyses. All authors contributed to discussion, interpretation of results and writing of the final version of the manuscript.
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This file is composed of five sections of experimental details, including Supplementary Schemes 1–3, Figs. 1–303 and Tables 1–109, and References.
Supplementary Video 1
Rotation of the 3D homochiral product e.e. prediction figure. Simulations of homochiral product 3 final e.e. for reaction of equimolar 1 and 2 with various initial e.e. of 1 and 2 at different diasterselectivities.
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Deng, M., Yu, J. & Blackmond, D.G. Symmetry breaking and chiral amplification in prebiotic ligation reactions. Nature 626, 1019–1024 (2024). https://doi.org/10.1038/s41586-024-07059-y
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DOI: https://doi.org/10.1038/s41586-024-07059-y
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