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Single-molecule force stability of the SARS-CoV-2–ACE2 interface in variants-of-concern

Nature Nanotechnology volume 19, pages 399–405 (2024)Cite this article

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Abstract

Mutations in SARS-CoV-2 have shown effective evasion of population immunity and increased affinity to the cellular receptor angiotensin-converting enzyme 2 (ACE2). However, in the dynamic environment of the respiratory tract, forces act on the binding partners, which raises the question of whether not only affinity but also force stability of the SARS-CoV-2–ACE2 interaction might be a selection factor for mutations. Using magnetic tweezers, we investigate the impact of amino acid substitutions in variants of concern (Alpha, Beta, Gamma and Delta) and on force-stability and bond kinetic of the receptor-binding domain–ACE2 interface at a single-molecule resolution. We find a higher affinity for all of the variants of concern (>fivefold) compared with the wild type. In contrast, Alpha is the only variant of concern that shows higher force stability (by 17%) compared with the wild type. Using molecular dynamics simulations, we rationalize the mechanistic molecular origins of this increase in force stability. Our study emphasizes the diversity of contributions to the transmissibility of variants and establishes force stability as one of the several factors for fitness. Understanding fitness advantages opens the possibility for the prediction of probable mutations, allowing a rapid adjustment of therapeutics, vaccines and intervention measures.

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Fig. 1: A single-molecule tethered ligand assay to study RBD binding to ACE2 for VOCs of SARS-CoV-2.
Fig. 2: Effects of VOCs on interface force stability and affinity.
Fig. 3: Effects of VOCs on the contact network at the RBD–ACE2 interface.

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Source data are provided with this paper. Additional data can be obtained from the corresponding author upon request.

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Acknowledgements

We thank M. Bos, J. de Graf and D. Dulin for helpful discussions and L. Schendel, N. Beier, B. Böck, E. Durner, S. D. Pritzl and C. Körösy for help with experiments. This study was supported by German Research Foundation Projects 386143268 and 111166240, a Human Frontier Science Program Cross Disciplinary Fellowship (LT000395/2020C); European Molecular Biology Organization Non-Stipendiary long-term fellowship (ALTF 1047-2019) to L.F.M.; ERC Consolidator grant ‘ProForce’; and the Physics Department of LMU Munich. R.C.B., P.S.F.C.G. and M.C.R.M. are supported by the National Science Foundation under grant MCB-2143787, by start-up funds provided by Auburn University, and R.C.B. additionally receives support from the National Institute of General Medical Sciences (NIGMS) of NIH through grant R24-GM145965.

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Author notes

  1. These authors contributed equally: Magnus S. Bauer, Sophia Gruber, Adina Hausch, Marcelo C. R. Melo, Priscila S. F. C. Gomes.

  2. These authors jointly supervised this work: Hermann E. Gaub, Rafael C. Bernardi, Jan Lipfert.

Authors and Affiliations

  1. Department of Physics and Center for NanoScience (CeNS), LMU Munich, Munich, Germany

    Magnus S. Bauer, Sophia Gruber, Adina Hausch, Thomas Nicolaus, Hermann E. Gaub & Jan Lipfert

  2. Department of Chemical Engineering, Stanford University, Stanford, CA, USA

    Magnus S. Bauer

  3. Department of Biochemistry, University of Washington, Seattle, WA, USA

    Magnus S. Bauer & Lukas F. Milles

  4. Institute for Protein Design, University of Washington, Seattle, WA, USA

    Magnus S. Bauer & Lukas F. Milles

  5. Center for Protein Assemblies, TUM School of Natural Sciences, Technical University of Munich, Munich, Germany

    Adina Hausch

  6. Department of Physics, Auburn University, Auburn, AL, USA

    Marcelo C. R. Melo, Priscila S. F. C. Gomes & Rafael C. Bernardi

  7. Department of Physics and Debye Institute for Nanomaterials Science, Utrecht University, Utrecht, The Netherlands

    Jan Lipfert

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Contributions

M.S.B., S.G., A.H., M.C.R.M., P.S.F.C.G., H.E.G., R.C.B. and J.L. designed the research. M.S.B., S.G. and A.H. built the instruments and performed the experiments. P.S.F.C.G., M.C.R.M. and R.C.B. performed and analysed the simulations. M.S.B., S.G., A.H., L.F.M. and T.N. contributed the new reagents and analytic tools. M.S.B., S.G. and A.H. analysed the experimental data. M.S.B., S.G., A.H., M.C.R.M., P.S.F.C.G., H.E.G., R.C.B. and J.L. wrote the paper with input from all authors.

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Correspondence to Jan Lipfert.

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Supplementary Figs. 1–13, Tables 1 and 2, references and full protein sequences.

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Source Data Fig. 1

Example results from MT force spectroscopy: fraction bound versus force determined by MT: example magnetic traces, lifetimes bound and dissociated versus force from the MT data. Source Data Fig. 2 Results from MT force spectroscopy and affinity measurements for VOCs. Source Data Fig. 3 Results from the correlation analysis based on MD simulations.

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Bauer, M.S., Gruber, S., Hausch, A. et al. Single-molecule force stability of the SARS-CoV-2–ACE2 interface in variants-of-concern. Nat. Nanotechnol. 19, 399–405 (2024). https://doi.org/10.1038/s41565-023-01536-7

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