Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Chemical fuels for molecular machinery

Abstract

Chemical reaction networks that transform out-of-equilibrium ‘fuel’ to ‘waste’ are the engines that power the biomolecular machinery of the cell. Inspired by such systems, autonomous artificial molecular machinery is being developed that functions by catalysing the decomposition of chemical fuels, exploiting kinetic asymmetry to harness energy released from the fuel-to-waste reaction to drive non-equilibrium structures and dynamics. Different aspects of chemical fuels profoundly influence their ability to power molecular machines. Here we consider the structure and properties of the fuels that biology has evolved and compare their features with those of the rudimentary synthetic chemical fuels that have so far been used to drive autonomous non-equilibrium molecular-level dynamics. We identify desirable, but context-specific, traits for chemical fuels together with challenges and opportunities for the design and invention of new chemical fuels to power synthetic molecular machinery and other dissipative nanoscale processes.

Your institute does not have access to this article

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Fig. 1: Chemically fuelled molecular dynamics.
Fig. 2: Chemical fuels used to power autonomous biological and synthetic molecular machinery.
Fig. 3: Chemical fuels for dissipative supramolecular assembly and macrocyclization.
Fig. 4: Chemical fuels for non-autonomous and non-directional molecular machinery.
Fig. 5: Molecular machines driven by chemical fuel pulses.
Fig. 6: Transition states for fuel-to-waste reactions mediated by molecular machines.

References

  1. Ragazzon, G. & Prins, L. J. Energy consumption in chemical fuel-driven self-assembly. Nat. Nanotechnol. 13, 882–889 (2018).

    CAS  PubMed  Article  Google Scholar 

  2. Das, K., Gabrielli, L. & Prins, L. J. Chemically fueled self‐assembly in biology and chemistry. Angew. Chem. Int. Ed. 60, 20120–20143 (2021).

    CAS  Article  Google Scholar 

  3. Biagini, C. & Di Stefano, S. Abiotic chemical fuels for the operation of molecular machines. Angew. Chem. Int. Ed. 59, 8344–8354 (2020).

    CAS  Article  Google Scholar 

  4. Astumian, R. D., Mukherjee, S. & Warshel, A. The physics and physical chemistry of molecular machines. ChemPhysChem 17, 1719–1741 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  5. Brown, A. I. & Sivak, D. A. Theory of nonequilibrium free energy transduction by molecular machines. Chem. Rev. 120, 434–459 (2020).

    CAS  PubMed  Article  Google Scholar 

  6. Amano, S., Borsley, S., Leigh, D. A. & Sun, Z. Chemical engines: driving systems away from equilibrium through catalyst reaction cycles. Nat. Nanotechnol. 16, 1057–1067 (2021).

    CAS  PubMed  Article  Google Scholar 

  7. Kay, E. R., Leigh, D. A. & Zerbetto, F. Synthetic molecular motors and mechanical machines. Angew. Chem. Int. Ed. 46, 72–191 (2007).

    CAS  Article  Google Scholar 

  8. Aprahamian, I. The future of molecular machines. ACS Cent. Sci. 6, 347–358 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  9. Erbas-Cakmak, S., Leigh, D. A., McTernan, C. T. & Nussbaumer, A. L. Artificial molecular machines. Chem. Rev. 115, 10081–10206 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  10. Wilson, M. R. et al. An autonomous chemically fuelled small-molecule motor. Nature 534, 235–240 (2016).

    CAS  PubMed  Article  Google Scholar 

  11. Amano, S., Fielden, S. D. P. & Leigh, D. A. A catalysis-driven artificial molecular pump. Nature 594, 529–534 (2021).

    CAS  PubMed  Article  Google Scholar 

  12. Borsley, S., Leigh, D. A. & Roberts, B. M. W. A doubly kinetically-gated information ratchet autonomously driven by carbodiimide hydration. J. Am. Chem. Soc. 143, 4414–4420 (2021).

    CAS  PubMed  Article  Google Scholar 

  13. Borsley, S., Kreidt, E., Leigh, D. A. & Roberts, B. M. W. Autonomous fuelled directional rotation about a covalent single bond. Nature 604, 80–85 (2022).

    CAS  PubMed  Article  Google Scholar 

  14. van Esch, J. H., Klajn, R. & Otto, S. Chemical systems out of equilibrium. Chem. Soc. Rev. 46, 5474–5475 (2017).

    PubMed  Article  Google Scholar 

  15. Baroncini, M., Silvi, S. & Credi, A. Photo- and redox-driven artificial molecular motors. Chem. Rev. 120, 200–268 (2020).

    CAS  PubMed  Article  Google Scholar 

  16. Roke, D., Wezenberg, S. J. & Feringa, B. L. Molecular rotary motors: unidirectional motion around double bonds. Proc. Natl Acad. Sci. USA 115, 9423–9431 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  17. Pezzato, C. et al. Controlling dual molecular pumps electrochemically. Angew. Chem. Int. Ed. 57, 9325–9329 (2018).

    CAS  Article  Google Scholar 

  18. Howe, E. N. W. & Gale, P. A. Fatty acid fueled transmembrane chloride transport. J. Am. Chem. Soc. 141, 10654–10660 (2019).

    CAS  PubMed  Article  Google Scholar 

  19. Weißenfels, M., Gemen, J. & Klajn, R. Dissipative self-assembly: fueling with chemicals versus light. Chem 7, 23–37 (2021).

    Article  CAS  Google Scholar 

  20. Walsh, C. T., Tu, B. P. & Tang, Y. Eight kinetically stable but thermodynamically activated molecules that power cell metabolism. Chem. Rev. 118, 1460–1494 (2018).

    CAS  PubMed  Article  Google Scholar 

  21. Toropova, K. et al. Structure of the dynein-2 complex and its assembly with intraflagellar transport trains. Nat. Struct. Mol. Biol. 26, 823–829 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  22. Astumian, R. D. Kinetic asymmetry allows macromolecular catalysts to drive an information ratchet. Nat. Commun. 10, 3837 (2019).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  23. Amano, S. et al. Insights from an information thermodynamics analysis of a synthetic molecular motor. Nat. Chem. 14, 530–537 (2022).

    CAS  PubMed  Article  Google Scholar 

  24. Boekhoven, J., Hendriksen, W. E., Koper, G. J. M., Eelkema, R. & van Esch, J. H. Transient assembly of active materials fueled by a chemical reaction. Science 349, 1075–1079 (2015).

    CAS  PubMed  Article  Google Scholar 

  25. Tena-Solsona, M. et al. Non-equilibrium dissipative supramolecular materials with a tunable lifetime. Nat. Commun. 8, 15895 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  26. Kariyawasam, L. S. & Hartley, C. S. Dissipative assembly of aqueous carboxylic acid anhydrides fueled by carbodiimides. J. Am. Chem. Soc. 139, 11949–11955 (2017).

    CAS  PubMed  Article  Google Scholar 

  27. Kariyawasam, L. S., Hossain, M. M. & Hartley, C. S. The transient covalent bond in abiotic nonequilibrium systems. Angew. Chem. Int. Ed. 60, 12648–12658 (2021).

    CAS  Article  Google Scholar 

  28. Rieß, B., Grötsch, R. K. & Boekhoven, J. The design of dissipative molecular assemblies driven by chemical reaction cycles. Chem 6, 552–578 (2020).

    Article  CAS  Google Scholar 

  29. Wilson, D. A., Nolte, R. J. M. & van Hest, J. C. M. Autonomous movement of platinum-loaded stomatocytes. Nat. Chem. 4, 268–274 (2012).

    CAS  PubMed  Article  Google Scholar 

  30. Sorrenti, A., Leira-Iglesias, J., Markvoort, A. J., de Greef, T. F. A. & Hermans, T. M. Non-equilibrium supramolecular polymerization. Chem. Soc. Rev. 46, 5476–5490 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  31. Leng, Z., Peng, F. & Hao, X. Chemical-fuel-driven assembly in macromolecular science: recent advances and challenges. ChemPlusChem 85, 1190–1199 (2020).

    CAS  PubMed  Article  Google Scholar 

  32. Merindola, R. & Walther, A. Materials learning from life: concepts for active, adaptive and autonomous molecular systems. Chem. Soc. Rev. 46, 5588–5619 (2017).

    Article  Google Scholar 

  33. Penocchio, E., Rao, R. & Esposito, M. Thermodynamic efficiency in dissipative chemistry. Nat. Commun. 10, 3865 (2019).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  34. Biagini, C. et al. Dissipative catalysis with a molecular machine. Angew. Chem. Int. Ed. 58, 9876–9880 (2019).

    CAS  Article  Google Scholar 

  35. Berrocal, J. A., Biagini, C., Mandolini, L. & Di Stefano, S. Coupling of the decarboxylation of 2-cyano-2-phenylpropanoic acid to large-amplitude motions: a convenient fuel for an acid–base-operated molecular switch. Angew. Chem. Int. Ed. 55, 6997–7001 (2016).

    CAS  Article  Google Scholar 

  36. Erbas-Cakmak, S. et al. Rotary and linear molecular motors driven by pulses of a chemical fuel. Science 358, 340–343 (2017).

    CAS  PubMed  Article  Google Scholar 

  37. Shi, Q. & Chen, C.-F. Step-by-step reaction-powered mechanical motion triggered by a chemical fuel pulse. Chem. Sci. 10, 2529–2533 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  38. Kelly, T. R., Tellitu, I. & Sestelo, J. P. In search of molecular ratchets. Angew. Chem. Int. Ed. Engl. 36, 1866–1868 (1997).

    CAS  Article  Google Scholar 

  39. Kelly, T. R. Progress toward a rationally designed molecular motor. Acc. Chem. Res. 34, 514–522 (2001).

    CAS  PubMed  Article  Google Scholar 

  40. Davis, A. P. Tilting at windmills? The Second Law survives. Angew. Chem. Int. Ed. Engl. 37, 909–910 (1998).

    CAS  PubMed  Article  Google Scholar 

  41. Feynman, R. P., Leighton, R. B. & Sands, M. The Feynman Lectures on Physics, Vol. 1 (Addison-Wesley, 1963).

  42. Kelly, T. R., De Silva, H. & Silva, R. A. Unidirectional rotary motion in a molecular system. Nature 401, 150–152 (1999).

    CAS  PubMed  Article  Google Scholar 

  43. Alvarez-Pérez, M., Goldup, S. M., Leigh, D. A. & Slawin, A. M. Z. A chemically-driven molecular information ratchet. J. Am. Chem. Soc. 130, 1836–1838 (2008).

    PubMed  Article  CAS  Google Scholar 

  44. Carlone, A., Goldup, S. M., Lebrasseur, N., Leigh, D. A. & Wilson, A. A three-compartment chemically-driven molecular information ratchet. J. Am. Chem. Soc. 134, 8321–8323 (2012).

    CAS  PubMed  Article  Google Scholar 

  45. Fletcher, S. P., Dumur, F., Pollard, M. M. & Feringa, B. L. A reversible, unidirectional molecular rotary motor driven by chemical energy. Science 310, 80–82 (2005).

    CAS  PubMed  Article  Google Scholar 

  46. Pan, J., Li, F., Cha, T.-G., Chen, H. & Choi, J. H. Recent progress on DNA based walkers. Curr. Opin. Biotechnol. 34, 56–64 (2015).

    PubMed  Article  CAS  Google Scholar 

  47. Valero, J. & Škugor, M. Mechanisms, methods of tracking and applications of DNA walkers: a review. Chemphyschem. 21, 1971–1988 (2020).

    CAS  PubMed  Article  Google Scholar 

  48. Bath, J., Green, S. J., Allen, K. E. & Turberfield, A. J. Mechanism for a directional, processive, and reversible DNA motor. Small 5, 1513–1516 (2009).

    CAS  PubMed  Article  Google Scholar 

  49. Mock, W. L. & Ochwat, K. J. Theory and example of a small-molecule motor. J. Phys. Org. Chem. 16, 175–182 (2003).

    CAS  Article  Google Scholar 

  50. Berná, J., Alajarín, M. & Orenes, R.-A. Azodicarboxamides as template binding motifs for the building of hydrogen-bonded molecular shuttles. J. Am. Chem. Soc. 132, 10741–10747 (2010).

    PubMed  Article  CAS  Google Scholar 

  51. Li, C.-B. & Toyabe, S. Efficiencies of molecular motors: a comprehensible overview. Biophys. Rev. 12, 419–423 (2020).

    PubMed  PubMed Central  Article  Google Scholar 

  52. Rosing, J. & Slater, E. C. The value of ΔG° for the hydrolysis of ATP. Biochim. Biophys. Acta Bioenerg. 267, 275–290 (1972).

    CAS  Article  Google Scholar 

  53. Westheimer, F. H. Why nature chose phosphates. Science 235, 1173–1178 (1987).

    CAS  PubMed  Article  Google Scholar 

  54. Mitchison, T. & Kirschner, M. Dynamic instability of microtubule growth. Nature 312, 237–242 (1984).

    CAS  PubMed  Article  Google Scholar 

  55. Dhiman, S., Jain, A. & George, S. J. Transient helicity: fuel‐driven temporal control over conformational switching in a supramolecular polymer. Angew. Chem. Int. Ed. 56, 1329–1333 (2017).

    CAS  Article  Google Scholar 

  56. Watson, M. A. & Cockroft, S. L. An autonomously reciprocating transmembrane nanoactuator. Angew. Chem. Int. Ed. 55, 1345–1349 (2016).

    CAS  Article  Google Scholar 

  57. Wolfenden, R. & Snider, M. J. The depth of chemical time and the power of enzymes as catalysts. Acc. Chem. Res. 34, 938–945 (2001).

    CAS  PubMed  Article  Google Scholar 

  58. Kiani, F. A. & Fischer, S. Stabilization of the ADP/metaphosphate intermediate during ATP hydrolysis in pre-power stroke myosin. J. Biol. Chem. 288, 35569–35580 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  59. Beis, I. & Newsholme, E. A. The contents of adenine nucleotides, phosphagens and some glycolytic intermediates in resting muscles from vertebrates and invertebrates. Biochem. J. 152, 23–32 (1975).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  60. Kornberg, A. For the Love of Enzymes: Odyssey of a Biochemist (Harvard Univ. Press, 1989).

  61. Agapakis, C. M., Boyle, P. M. & Silver, P. A. Natural strategies for the spatial optimization of metabolism in synthetic biology. Nat. Chem. Biol. 8, 527–535 (2012).

    CAS  PubMed  Article  Google Scholar 

  62. Zecchin, A., Stapor, P. C., Goveia, J. & Carmeliet, P. Metabolic pathway compartmentalization: an underappreciated opportunity? Curr. Opin. Biotechnol. 34, 73–81 (2015).

    CAS  PubMed  Article  Google Scholar 

  63. Bader, A. & Cockroft, S. L. Conformational enhancement of fidelity in toehold-sequestered DNA nanodevices. Chem. Commun. 56, 5135–5138 (2020).

    CAS  Article  Google Scholar 

  64. Boissan, M. et al. Nucleoside diphosphate kinases fuel dynamin superfamily proteins with GTP for membrane remodeling. Science 344, 1510–1515 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  65. Ma, B. & Nussinov, R. Enzyme dynamics point to stepwise conformational selection in catalysis. Curr. Opin. Chem. Biol. 14, 652–659 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  66. Kamerlin, S. C. & Warshel, A. At the dawn of the 21st century: is dynamics the missing link for understanding enzyme catalysis? Proteins 78, 1339–1375 (2009).

    Article  CAS  Google Scholar 

  67. Blanco, V., Leigh, D. A. & Marcos, V. Artificial switchable catalysts. Chem. Soc. Rev. 44, 5341–5370 (2015).

    CAS  PubMed  Article  Google Scholar 

  68. Herges, R. Molecular assemblers: molecular machines performing chemical synthesis. Chem. Sci. 11, 9048–9055 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  69. Abrahams, J. P., Leslie, A. G. W., Lutter, R. & Walker, J. E. Structure at 2.8 Å resolution of F1-ATPase from bovine heart mitochondria. Nature 370, 621–628 (1994).

    CAS  PubMed  Article  Google Scholar 

  70. Hosseini, M. W. et al. Supramolecular catalysis: polyammonium macrocycles as enzyme mimics for phosphoryl transfer in ATP hydrolysis. J. Am. Chem. Soc. 111, 6330–6335 (1989).

    CAS  Article  Google Scholar 

  71. Efremov, A. & Wang, Z. Universal optimal working cycles of molecular motors. Phys. Chem. Chem. Phys. 13, 6223–6233 (2011).

    CAS  PubMed  Article  Google Scholar 

  72. Albaugh, A. & Gingrich, T. R. Simulating a chemically-fueled molecular motor with nonequilibrium molecular dynamics. Nat. Commun. 13, 2204 (2021).

    Article  CAS  Google Scholar 

  73. SantaLucia, J. Jr. & Hicks, D. The thermodynamics of DNA structural motifs. Annu. Rev. Biophys. Biomol. Struct. 33, 415–440 (2004).

    CAS  PubMed  Article  Google Scholar 

  74. Clancy, B. E., Behnke-Parks, W. M., Andreasson, J. O. L., Rosenfeld, S. S. & Block, S. M. A universal pathway for kinesin stepping. Nat. Struct. Mol. Biol. 18, 1020–1027 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  75. Nishiyama, M., Higuchi, H. & Yanagida, T. Chemomechanical coupling of the forward and backward steps of single kinesin molecules. Nat. Cell Biol. 4, 790–797 (2002).

    CAS  PubMed  Article  Google Scholar 

  76. Tordini, F. et al. Theoretical study of hydration of cyanamide and carbodiimide. J. Phys. Chem. A 107, 1188–1196 (2003).

    CAS  Article  Google Scholar 

  77. Singh, N., Formon, G. J. M., De Piccoli, S. & Hermans, T. M. Devising synthetic reaction cycles for dissipative nonequilibrium self-assembly. Adv. Mater. 32, 1906834 (2020).

    CAS  Article  Google Scholar 

  78. Bazhin, N. The essence of ATP coupling. ISRN Biochem. 2012, 827604 (2012).

    PubMed  PubMed Central  Article  Google Scholar 

  79. Bonora, M. et al. ATP synthesis and storage. Purinergic Signal. 8, 343–357 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  80. Sorrenti, A., Leira-Iglesias, J., Sato, A. & Hermans, T. M. Non-equilibrium steady states in supramolecular polymerization. Nat. Commun. 8, 15899 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  81. Popson, M. S., Dimri, M. & Borger, J. Biochemistry, Heat and Calories (StatPearls, 2021).

  82. Ugajin, A. et al. Detection of neural activity in the brains of Japanese honeybee workers during the formation of a ‘hot defensive bee ball’. PLoS One 7, e32902 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  83. Zhang, L., Marcos, V. & Leigh, D. A. Molecular machines with bio-inspired mechanisms. Proc. Natl Acad. Sci. USA 115, 9397–9404 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  84. De, S. & Klajn, R. Dissipative self-assembly driven by the consumption of chemical fuels. Adv. Mater. 30, 1706750 (2018).

    Article  CAS  Google Scholar 

  85. Watson, M. A. & Cockroft, S. L. Man-made molecular machines: membrane bound. Chem. Soc. Rev. 45, 6118–6129 (2016).

    CAS  PubMed  Article  Google Scholar 

  86. Langton, M. J. Engineering of stimuli responsive lipid-bilayer membranes using supramolecular systems. Nat. Rev. Chem. 5, 46–61 (2021).

    CAS  Article  Google Scholar 

  87. Xu, X. et al. Boric acid‐fueled ATP synthesis by F0F1 ATP synthase reconstituted in a supramolecular architecture. Angew. Chem. Int. Ed. 60, 7617–7620 (2021).

    CAS  Article  Google Scholar 

  88. Dhiman, S., Jain, A., Kumar, M. & George, S. J. Adenosine-phosphate-fueled, temporally programmed supramolecular polymers with multiple transient states. J. Am. Chem. Soc. 139, 16568–16575 (2017).

    CAS  PubMed  Article  Google Scholar 

  89. Faulkner, A., van Leeuwen, T., Feringa, B. L. & Wezenberg, S. J. Allosteric regulation of the rotational speed in a light-driven molecular motor. J. Am. Chem. Soc. 138, 13597–13603 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  90. Guo, H., Suzuki, T. & Rubinstein, J. L. Structure of a bacterial ATP synthase. eLife 8, e43128 (2019).

    PubMed  PubMed Central  Article  Google Scholar 

  91. Schmidt, H., Zalyte, R., Urnavicius, L. & Carter, A. P. Structure of human cytoplasmic dynein-2 primed for its power stroke. Nature 518, 435–438 (2015).

    CAS  PubMed  Article  Google Scholar 

Download references

Acknowledgements

We thank the Engineering and Physical Sciences Research Council (EPSRC; grant number EP/P027067/1) and the European Research Council (ERC; Advanced Grant number 786630) for funding, and S. Amano and E. Kreidt for useful discussions. D.A.L. is a Royal Society Research Professor.

Author information

Authors and Affiliations

Authors

Contributions

All authors contributed to the writing of the manuscript.

Corresponding author

Correspondence to David A. Leigh.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Chemistry thanks Scott Hartley, Xiang Hao and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Borsley, S., Leigh, D.A. & Roberts, B.M.W. Chemical fuels for molecular machinery. Nat. Chem. 14, 728–738 (2022). https://doi.org/10.1038/s41557-022-00970-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41557-022-00970-9

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing