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Evolution of complex chemical mixtures reveals combinatorial compression and population synchronicity

Nature Chemistry volume 17, pages 590–597 (2025)Cite this article

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Abstract

Many open questions about the origins of life are centred on the generation of complex chemical species. Past work has characterized specific chemical reactions that might lead to biological molecules. Here we establish an experimental model of chemical evolution to investigate general processes by which chemical systems continuously change. We used water as a chemical reactant, product and medium. We leveraged oscillating water activity at near-ambient temperatures to cause ratcheting of near-equilibrium reactions in mixtures of organic molecules containing carboxylic acids, amines, thiols and hydroxyl groups. Our system (1) undergoes continuous change with transitions to new chemical spaces while not converging throughout the experiment; (2) demonstrates combinatorial compression with stringent chemical selection; and (3) displays synchronicity of molecular populations. Our results suggest that chemical evolution and selection can be observed in organic mixtures and might ultimately be adapted to produce a broad array of molecules with novel structures and functions.

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Fig. 1: Peptide bonds are formed catalytically.
Fig. 2: Nine chemical components were used to investigate chemical evolution.
Fig. 3: Chemical change is observed during wet–dry cycling.
Fig. 4: Combinatorial compression is observed at low temperature.
Fig. 5: Combinatorial compression is observed at low temperatures while combinatorial explosion is observed at high temperatures.
Fig. 6: Synchronous changes in chemical populations are observed during wet–dry cycling.

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Data availability

The data supporting the findings of this study are available within the article and its Supplementary Information.

Code availability

Our Python code for calculating continuous chemical change—which corrects the chromatogram baseline, and identifies and integrates peaks—is available at: https://github.com/HUJI-MFP/HPLC_automatic_analysis/blob/main/HPLC_python.py.

References

  1. Bell, E. A., Boehnke, P., Harrison, T. M. & Mao, W. L. Potentially biogenic carbon preserved in a 4.1 billion-year-old zircon. Proc. Natl Acad. Sci. USA 112, 14518–14521 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Orgel, L. E. The origin of life on the earth. Sci. Am. 271, 76–83 (1994).

    Article  CAS  PubMed  Google Scholar 

  3. Trainer, M. G. et al. Organic haze on Titan and the early Earth. Proc. Natl Acad. Sci. USA 103, 18035–18042 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Reed, N. W., Wing, B. A., Tolbert, M. A. & Browne, E. C. Trace H2S promotes organic aerosol production and organosulfur compound formation in archean analog haze photochemistry experiments. Geophys. Res. Lett. 49, e2021GL097032 (2022).

    Article  CAS  Google Scholar 

  5. Zahnle, K. J., Lupu, R., Catling, D. C. & Wogan, N. Creation and evolution of impact-generated reduced atmospheres of early Earth. Planetary Sci. J. 1, 11 (2020).

    Article  CAS  Google Scholar 

  6. Hud, N. V., Cafferty, B. J., Krishnamurthy, R. & Williams, L. D. The origin of RNA and ‘my grandfather’s axe’. Chem. Biol. 20, 466–474 (2013).

    Article  CAS  PubMed  Google Scholar 

  7. Brack, A. Selective emergence and survival of early polypeptides in water. Orig. Life Evol. Biosph. 17, 367–379 (1987).

    Article  CAS  PubMed  Google Scholar 

  8. Schneider, C. et al. Noncanonical RNA nucleosides as molecular fossils of an early Earth—generation by prebiotic methylations and carbamoylations. Angew. Chem. Int. Ed. 57, 5943–5946 (2018).

    Article  CAS  Google Scholar 

  9. Deamer, D. The role of lipid membranes in life’s origin. Life 7, 5 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  10. Kim, S. C. et al. A model for the emergence of RNA from a prebiotically plausible mixture of ribonucleotides, arabinonucleotides, and 2′-deoxynucleotides. J. Am. Chem. Soc. 142, 2317–2326 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Frenkel-Pinter, M. et al. Selective incorporation of proteinaceous over nonproteinaceous cationic amino acids in model prebiotic oligomerization reactions. Proc. Natl Acad. Sci. USA 116, 16338–16346 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Runnels, C. M. et al. Folding, assembly, and persistence: the essential nature and origins of biopolymers. J. Mol. Evol. 86, 598–610 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Cleaves II, H. J. The origin of the biologically coded amino acids. J. Theor. Biol. 263, 490–498 (2010).

    Article  Google Scholar 

  14. Vincent, L. et al. Chemical ecosystem selection on mineral surfaces reveals long-term dynamics consistent with the spontaneous emergence of mutual catalysis. Life 9, 80 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Cafferty, B. J. et al. Robustness, entrainment, and hybridization in dissipative molecular networks, and the origin of life. J. Am. Chem. Soc. 141, 8289–8295 (2019).

    Article  CAS  PubMed  Google Scholar 

  16. Segré, D., Ben-Eli, D. & Lancet, D. Compositional genomes: prebiotic information transfer in mutually catalytic noncovalent assemblies. Proc. Natl Acad. Sci. USA 97, 4112–4117 (2000).

    Article  PubMed  PubMed Central  Google Scholar 

  17. Kroiss, D., Ashkenasy, G., Braunschweig, A. B., Tuttle, T. & Ulijn, R. V. Catalyst: can systems chemistry unravel the mysteries of the chemical origins of life? Chem 5, 1917–1920 (2019).

    Article  CAS  Google Scholar 

  18. Ashkenasy, G., Hermans, T. M., Otto, S. & Taylor, A. F. Systems chemistry. Chem. Soc. Rev. 46, 2543–2554 (2017).

    Article  CAS  PubMed  Google Scholar 

  19. Guttenberg, N., Virgo, N., Chandru, K., Scharf, C. & Mamajanov, I. Bulk measurements of messy chemistries are needed for a theory of the origins of life. Philos. Trans. R. Soc. A 375, 20160347 (2017).

    Article  Google Scholar 

  20. Wołos, A. et al. Synthetic connectivity, emergence, and self-regeneration in the network of prebiotic chemistry. Science 369, eaaw1955 (2020).

    Article  PubMed  Google Scholar 

  21. Miao, X. et al. Kinetic selection in the out‐of‐equilibrium autocatalytic reaction networks that produce macrocyclic peptides. Angew. Chem. Int. Ed. 133, 20529–20538 (2021).

    Article  Google Scholar 

  22. Cao, Y. et al. Self‐synthesizing nanorods from dynamic combinatorial libraries against drug resistant cancer. Angew. Chem. Int. Ed. 133, 3099–3107 (2021).

    Article  Google Scholar 

  23. Komáromy, D., Nowak, P. & Otto, S. in Dynamic Covalent Chemistry: Principles, Reactions, and Applications 31–119 (Wiley, 2017).

  24. Chvykov, P. et al. Low rattling: a predictive principle for self-organization in active collectives. Science 371, 90–95 (2021).

    Article  CAS  PubMed  Google Scholar 

  25. Otto, S., Furlan, R. L. & Sanders, J. K. Selection and amplification of hosts from dynamic combinatorial libraries of macrocyclic disulfides. Science 297, 590–593 (2002).

    Article  CAS  PubMed  Google Scholar 

  26. Lam, R. T. et al. Amplification of acetylcholine-binding catenanes from dynamic combinatorial libraries. Science 308, 667–669 (2005).

    Article  CAS  PubMed  Google Scholar 

  27. Liu, B. et al. Complex molecules that fold like proteins can emerge spontaneously. J. Am. Chem. Soc. 141, 1685–1689 (2018).

    Article  PubMed Central  Google Scholar 

  28. Carnall, J. M. et al. Mechanosensitive self-replication driven by self-organization. Science 327, 1502–1506 (2010).

    Article  CAS  PubMed  Google Scholar 

  29. Kahana, A. & Lancet, D. Self-reproducing catalytic micelles as nanoscopic protocell precursors. Nat. Rev. Chem. 5, 870–878 (2021).

    Article  CAS  PubMed  Google Scholar 

  30. Mamajanov, I. et al. Ester formation and hydrolysis during wet–dry cycles: generation of far-from-equilibrium polymers in a model prebiotic reaction. Macromolecules 47, 1334–1343 (2014).

    Article  CAS  Google Scholar 

  31. Damer, B. & Deamer, D. The hot spring hypothesis for an origin of life. Astrobiology 20, 429–452 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  32. Foster, K., Hillman, B., Rajaei, V., Seng, K. & Maurer, S. Evolution of realistic organic mixtures for the origins of life through wet–dry cycling. Sci 4, 22 (2022).

    Article  CAS  Google Scholar 

  33. Li, Z. et al. The oligomerization of glucose under plausible prebiotic conditions. Orig. Life Evol. Biosph. 49, 225–240 (2019).

    Article  CAS  PubMed  Google Scholar 

  34. Jia, T. Z. et al. Incorporation of basic α-hydroxy acid residues into primitive polyester microdroplets for RNA segregation. Biomacromolecules 22, 1484–1493 (2021).

    Article  CAS  PubMed  Google Scholar 

  35. Jia, T. Z. & Chandru, K. Recent progress in primitive polyester synthesis and membraneless microdroplet assembly. Biophys. Physicobiol. 20, e200012 (2023).

    CAS  Google Scholar 

  36. Jia, T. Z. et al. Membraneless polyester microdroplets as primordial compartments at the origins of life. Proc. Natl Acad. Sci. USA 116, 15830–15835 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Rodriguez-Garcia, M. et al. Formation of oligopeptides in high yield under simple programmable conditions. Nat. Commun. 6, 8385 (2015).

    Article  CAS  PubMed  Google Scholar 

  38. Forsythe, J. G. et al. Ester-mediated amide bond formation driven by wet–dry cycles: a possible path to polypeptides on the prebiotic earth. Angew. Chem. Int. Ed. 54, 9871–9875 (2015).

    Article  CAS  Google Scholar 

  39. Yu, S. et al. Elongation of model prebiotic proto-peptides by continuous monomer feeding. Macromolecules 50, 9286–9294 (2017).

    Article  CAS  Google Scholar 

  40. Forsythe, J. G. et al. Surveying the sequence diversity of model prebiotic peptides by mass spectrometry. Proc. Natl Acad. Sci. USA 114, E7652–E7659 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Doran, D., Abul‐Haija, Y. M. & Cronin, L. Emergence of function and selection from recursively programmed polymerisation reactions in mineral environments. Angew. Chem. Int. Ed. 58, 11253–11256 (2019).

    Article  CAS  Google Scholar 

  42. Bouza, M. et al. Compositional characterization of complex protopeptide libraries via triboelectric nanogenerator orbitrap mass spectrometry. Rapid Commun. Mass Spectr. 33, 1293–1300 (2019).

    Article  CAS  Google Scholar 

  43. Frenkel-Pinter, M. et al. Mutually stabilizing interactions between proto-peptides and RNA. Nat. Commun. 11, 3137 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Frenkel-Pinter, M., Sargon, A. B., Glass, J. B., Hud, N. V. & Williams, L. D. Transition metals enhance prebiotic depsipeptide oligomerization reactions involving histidine. RSC Adv. 11, 3534–3538 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Frenkel-Pinter, M. et al. Thioesters provide a plausible prebiotic path to proto-peptides. Nat. Commun. 13, 2569 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Lago, I., Black, L., Wilfinger, M. & Maurer, S. E. Synthesis and characterization of amino acid decyl esters as early membranes for the origins of life. Membranes 12, 858 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Frenkel-Pinter, M., Samanta, M., Ashkenasy, G. & Leman, L. J. Prebiotic peptides: molecular hubs in the origin of life. Chem. Rev. 120, 4707–4765 (2020).

    Article  CAS  PubMed  Google Scholar 

  48. Asche, S., Cooper, G. J. T., Keenan, G., Mathis, C. & Cronin, L. A robotic prebiotic chemist probes long-term reactions of complexifying mixtures. Nat. Commun. 12, 3547 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Marshall, S. M. et al. Identifying molecules as biosignatures with assembly theory and mass spectrometry. Nat. Commun. 12, 3033 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Orgel, L. E. Prebiotic chemistry and the origin of the RNA world. Crit. Rev. Biochem. Mol. Biol. 39, 99–123 (2004).

    Article  CAS  PubMed  Google Scholar 

  51. Colón-Santos, S., Cooper, G. J. & Cronin, L. Taming combinatorial explosion of the formose reaction via recursion within mineral environments. ChemSystemsChem 1, e1900014 (2019).

  52. van Duppen, P., Daines, E., Robinson, W. E. & Huck, W. T. Dynamic environmental conditions affect the composition of a model prebiotic reaction network. J. Am. Chem. Soc. 145, 7559–7568 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  53. Virtanen, P. et al. SciPy 1.0: fundamental algorithms for scientific computing in Python. Nat. Methods 17, 261–272 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Yu, S. S. et al. Kinetics of prebiotic depsipeptide formation from the ester-amide exchange reaction. Phys. Chem. Chem. Phys. 18, 28441–28450 (2016).

    Article  CAS  PubMed  Google Scholar 

  55. Edri, R., Fisher, S., Menor‐Salvan, C., Williams, L. D. & Frenkel‐Pinter, M. Assembly‐driven protection from hydrolysis as key selective force during chemical evolution. FEBS Lett. 597, 2879–2896 (2023).

    Article  CAS  PubMed  Google Scholar 

  56. Kensil, C. R. & Dennis, E. A. Alkaline hydrolysis of phospholipids in model membranes and the dependence on their state of aggregation. Biochemistry 20, 6079–6085 (1981).

    Article  CAS  PubMed  Google Scholar 

  57. Abkevich, V. I., Gutin, A. M. & Shakhnovich, E. I. How the first biopolymers could have evolved. Proc. Natl Acad. Sci. USA 93, 839–844 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Prusiner, S. B. Prions. Proc. Natl Acad. Sci. USA 95, 13363–13383 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Nahvi, A. et al. Genetic control by a metabolite binding mRNA. Chem. Biol. 9, 1043–1049 (2002).

    Article  CAS  PubMed  Google Scholar 

  60. Frenkel-Pinter, M., Rajaei, V., Glass, J. B., Hud, N. V. & Williams, L. D. Water and life: the medium is the message. J. Mol. Evol. 89, 2–11 (2021).

  61. Lowry, T. & Richardson, K. Mechanism and Theory in Organic Chemistry (Harper & Row, 1981).

  62. Jacob, F. Evolution and tinkering. Science 196, 1161–1166 (1977).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank N. Hud, M.G. Finn, G. Schuster, M. Grover, M. Travisano, D. Lancet and E. Smith for helpful comments. Funding: This research was supported by the National Science Foundation (grant no. 1724274 to L.D.W.), NASA Center for Integration of the Origins of Life (grant no. 80NSSC24K0344), the Azrieli Foundation Early Career Faculty Grant (to M.F.P.), the Israel Science Foundation grant (grant no. 1611/22 to M.F.P.), the Minerva Foundation (to M.F.P.) and FEBS Foundation Excellence Award (to M.F.P.).

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Authors and Affiliations

  1. NASA Center for Integration of the Origins of Life, Atlanta, GA, USA

    Kavita Matange, Vahab Rajaei, Pau Capera-Aragones, John T. Costner, Adelaide Robertson, Jennifer Seoyoung Kim, Anton S. Petrov, Jessica C. Bowman, Loren Dean Williams & Moran Frenkel-Pinter

  2. School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA, USA

    Kavita Matange, Vahab Rajaei, Pau Capera-Aragones, John T. Costner, Adelaide Robertson, Jennifer Seoyoung Kim, Anton S. Petrov, Jessica C. Bowman & Loren Dean Williams

  3. Institute of Chemistry, The Hebrew University of Jerusalem, Jerusalem, Israel

    Pau Capera-Aragones & Moran Frenkel-Pinter

  4. NSF-NASA Center of Chemical Evolution, Atlanta, GA, USA

    Anton S. Petrov, Jessica C. Bowman & Loren Dean Williams

  5. The Center for Nanoscience and Nanotechnology, The Hebrew University of Jerusalem, Jerusalem, Israel

    Moran Frenkel-Pinter

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  1. Kavita Matange
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Contributions

M.F.P. and K.M. performed dry-down and wet–dry cycling experiments. M.P.F., K.M. and V.R. performed chemical analysis. K.M., A.R., J.S.K. and M.F.P. performed analysis of HPLC data. P.C.A. wrote a Python code for automatic analysis of HPLC data. V.R. performed the NMR analysis. A.S.P. and J.T.C. performed analysis of MS data. M.F.P., K.M. and L.D.W. formulated models, and conceived and designed experiments. M.F.P., K.M., V.R., J.C.B., P.C.A. and L.D.W. wrote the paper.

Corresponding authors

Correspondence to Loren Dean Williams or Moran Frenkel-Pinter.

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Nature Chemistry thanks David Baum, Shawn McGlynn and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information

Methods, Supplementary Figs. 1–44 and Table 1.

Supplementary Data 1

Mass spectrometry data from HPLC separations of wet–dry cycling experiments.

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Matange, K., Rajaei, V., Capera-Aragones, P. et al. Evolution of complex chemical mixtures reveals combinatorial compression and population synchronicity. Nat. Chem. 17, 590–597 (2025). https://doi.org/10.1038/s41557-025-01734-x

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