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Helical protein nanotubules assembled from sacrificial supramolecular polymers

Nature Synthesis volume 4, pages 562–572 (2025)Cite this article

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Abstract

Precise helical supramolecular polymers of proteins can only be achieved in vivo by tuning complex, competing supramolecular interactions. This formation suggests a level of cellular control that defines functional structures with high fidelity. Achieving such a phenomenon through synthetic reactions is a challenge owing to the lack of native competing interactions. Here we report that synthetic self-assembled polymers spontaneously disassemble to trigger helical growth of protein units to form well-defined protein tubules in vitro. Cryogenic electron microscopy reconstruction at near-atomic resolution reveals uniform protein helical arrays rather than polymorphic arrays. These uniform arrays are similar to natural microtubules, and the aggregated structure of the sacrificed supramolecular ligands within the protein nanotubule is pentameric. The formation of the protein nanotubules, rather than supramolecular polymer of ligands, regulates the physical properties of the solution and the morphology of liposomes. It was shown that enthalpy–entropy compensation provided by the dissociation of aggregated ligands modulates the homogeneity of the helical pattern of the protein nanotubules, shedding light on the creation of sophisticated bionic materials.

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Fig. 1: Design of the sacrificial supramolecular polymer for protein supramolecular polymerization.
Fig. 2: Design and analysis of the LSPs for protein nanotubules.
Fig. 3: PSP induced by PE2Gal and the competition effect among them.
Fig. 4: Extended ligands design and molecular model for nanotubules.
Fig. 5: Kinetic and thermodynamic characterization of PSPs.

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Data availability

All data required to interpret, verify and extend the results are given in the paper and its Supplementary Information. The maps of nanotubules are deposited in the Electron Microscopy Data Bank under accession codes EMD-60193, EMD-60194 and EMD-60195 for ZE1Gal/SBA, EMD-60192 for BE1Gal/SBA and EMD-60191 for PE2Gal/SBA.

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Acknowledgements

G.C. and L.L. thank NSFC/China (grant nos. 52125303, 52403179, and 92356305 and 22431002), the National Key Research and Development Program of China (grant no. 2023YFA0915300) and Innovation Program of Shanghai Municipal Education Commission (grant no. 2023ZKZD02) for financial support. M.L. thanks NSFC/China (grant nos. 92156023 and 92356306) for financial support. This research is also supported by the Postdoctoral Fellowship Program of CPSF under grant no. GZC20240273. We thank the Shanghai Synchrotron Radiation Facility (Bio-SAXS: BL19U2) for the SAXS test. We also thank the Spallation Neutron Source Science Center in Dongguan for neutron scattering experiments with the help of H. Cheng, T. Zuo, H. Zhu and X. Liu.

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Authors and Affiliations

  1. State Key Laboratory of Molecular Engineering of Polymers and Department of Macromolecular Science, Fudan University, Shanghai, China

    Linfei Ye, Xiaoduo Dong, Long Li & Guosong Chen

  2. Shanghai Xuhui Central Hospital, Zhongshan-Xuhui Hospital, and the Shanghai Key Laboratory of Medical Epigenetics, the International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Institutes of Biomedical Sciences, Fudan University, Shanghai, China

    Chong Wang

  3. Polymer Program, Institute of Materials Science and Department of Chemistry, University of Connecticut, Storrs, CT, USA

    Yao Lin

  4. Department of Chemistry, Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials, Fudan University, Shanghai, China

    Myongsoo Lee

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Contributions

L.Y., L.L. and G.C. conceptualized and administered the project and wrote the paper. L.Y. performed the synthesis of all the ligands and studied the self-assembly of ligands and protein by spectroscopy experiments. L.L. performed the molecular dynamics simulations. L.Y. and X.D. performed the cryo-EM experiment. L.L. performed the cryo-EM images processing, model building and refinement. C.W. performed the microfluidics experiment. Y.L. and M.L. analysed and interpreted the results, and involved in revision of the paper.

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Correspondence to Long Li or Guosong Chen.

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Nature Synthesis thanks Huaimin Wang, Shiki Yagai and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Alison Stoddart, in collaboration with the Nature Synthesis team.

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Supplementary information

Supplementary Information

Supplementary Figs. 1–53, discussion, and Schemes 1 and 2.

Supplementary Data 1

Validation report of macromolecular structures.

Supplementary Data 2

Validation report of macromolecular structures.

Supplementary Data 3

Validation report of macromolecular structures.

Supplementary Data 4

Validation report of macromolecular structures.

Supplementary Data 5

Validation report of macromolecular structures.

Source data

Source Data Fig. 2

Statistical source data.

Source Data Fig. 3

Statistical source data.

Source Data Fig. 5

Statistical source data.

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Ye, L., Dong, X., Wang, C. et al. Helical protein nanotubules assembled from sacrificial supramolecular polymers. Nat. Synth 4, 562–572 (2025). https://doi.org/10.1038/s44160-024-00726-y

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