Force-tuned avidity of spike variant-ACE2 interactions viewed on the single-molecule level

Rong Zhu; Daniel Canena; Mateusz Sikora; Miriam Klausberger; Hannah Seferovic; Ahmad Reza Mehdipour; Lisa Hain; Elisabeth Laurent; Vanessa Monteil; Gerald Wirnsberger; Ralph Wieneke; Robert Tampé; Nikolaus F. Kienzl; Lukas Mach; Ali Mirazimi; Yoo Jin Oh; Josef M. Penninger; Gerhard Hummer; Peter Hinterdorfer

doi:10.1038/s41467-022-35641-3

Force-tuned avidity of spike variant-ACE2 interactions viewed on the single-molecule level

Rong Zhu
, Daniel Canena
, Mateusz Sikora
, Miriam Klausberger
, Hannah Seferovic
, Ahmad Reza Mehdipour
, Lisa Hain
, Elisabeth Laurent
, Vanessa Monteil
, Gerald Wirnsberger
, Ralph Wieneke
, Robert Tampé
, Nikolaus F. Kienzl
, Lukas Mach
, Ali Mirazimi
, Yoo Jin Oh
, Josef M. Penninger (Corresponding author)
, Gerhard Hummer (Corresponding author)
, Peter Hinterdorfer (Corresponding author)

Computational and Soft Matter Physics

Publications: Contribution to journal › Article › Peer Reviewed

Abstract

Recent waves of COVID-19 correlate with the emergence of the Delta and the Omicron variant. We report that the Spike trimer acts as a highly dynamic molecular caliper, thereby forming up to three tight bonds through its RBDs with ACE2 expressed on the cell surface. The Spike of both Delta and Omicron (B.1.1.529) Variant enhance and markedly prolong viral attachment to the host cell receptor ACE2, as opposed to the early Wuhan-1 isolate. Delta Spike shows rapid binding of all three Spike RBDs to three different ACE2 molecules with considerably increased bond lifetime when compared to the reference strain, thereby significantly amplifying avidity. Intriguingly, Omicron (B.1.1.529) Spike displays less multivalent bindings to ACE2 molecules, yet with a ten time longer bond lifetime than Delta. Delta and Omicron (B.1.1.529) Spike variants enhance and prolong viral attachment to the host, which likely not only increases the rate of viral uptake, but also enhances the resistance of the variants against host-cell detachment by shear forces such as airflow, mucus or blood flow. We uncover distinct binding mechanisms and strategies at single-molecule resolution, employed by circulating SARS-CoV-2 variants to enhance infectivity and viral transmission.

Original language	English
Article number	7926
Number of pages	17
Journal	Nature Communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-35641-3
Publication status	Published - Dec 2022

Funding

We thank Florian Krammer (Icahn School of Medicine at Mount Sinai, NY, USA) for providing the genetic constructs used for the production of recombinant SARS-CoV-2 Spike protein and RBD. Purified Spike and RBD as well as transfection‐grade mammalian expression plasmids were obtained from the reagent repository of the BOKU COVID‐19 Initiative. The BOKU Spin-off Novasign GmbH created and hosts the BOKU-COVID19 Portal (portal.boku-covid19.at) that enables researchers to access free samples of SARS-CoV-2 antigens described within this work. We acknowledge SuperMUC-NG computing allocation at the Leibniz Supercomputing Centre (M.S. and G.H.). We thank the Max Planck Society (M.S., A.R.M., and G.H.) for support and the Max Planck Computing Data Facility for computational resources. We further acknowledge funding from the German Research Foundation (TA157/12-1 to R.T.), the European Research Council (ERC Advanced Grant No. 789121 to R.T.), the Volkswagen Foundation (96 498 to R.W. and 96 496 to R.T.), and the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement no.101005026. The J.U. receives support from the European Union’s Horizon 2020 research and innovation program and EFPIA. J.M.P. has received funding from the T. von Zastrow foundation, the FWF Wittgenstein award (Z 271-B19), the Austrian Academy of Sciences, the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement No. 101005026, and the Canada 150 Research Chairs Program F18-01336, as well as the Canadian Institutes of Health Research COVID-19 grants F20-02343 and F20-02015. This work was further supported by funding from the Austrian National Foundation for Research, Technology, and Development and Research Department of the State of Upper Austria (Y.O.), from the FWF projects W1224 (N.F.K. and L.M.), V584 (Y.O.), P31599 (R.Z.), P30314 (P.H.), I3183 (P.H.), FWFP35166000 (M.K., P.H.), the WWTF grant LS19-029 (P.H., D.C.), the ÖAW fellowship STIP13202002 (L.H.), the European Union’s Horizon research and innovation program (grant no. H2020-MSCA-ITN-2016) under the Marie Skolodowska-Curie grant agreement No. 721874 (P.H. and D.C.), the FWF Schroedinger fellowship J4332-B28 (M.S.). We thank Florian Krammer (Icahn School of Medicine at Mount Sinai, NY, USA) for providing the genetic constructs used for the production of recombinant SARS-CoV-2 Spike protein and RBD. Purified Spike and RBD as well as transfection‐grade mammalian expression plasmids were obtained from the reagent repository of the BOKU COVID‐19 Initiative. The BOKU Spin-off Novasign GmbH created and hosts the BOKU-COVID19 Portal (portal.boku-covid19.at) that enables researchers to access free samples of SARS-CoV-2 antigens described within this work. We acknowledge SuperMUC-NG computing allocation at the Leibniz Supercomputing Centre (M.S. and G.H.). We thank the Max Planck Society (M.S., A.R.M., and G.H.) for support and the Max Planck Computing Data Facility for computational resources. We further acknowledge funding from the German Research Foundation (TA157/12-1 to R.T.), the European Research Council (ERC Advanced Grant No. 789121 to R.T.), the Volkswagen Foundation (96 498 to R.W. and 96 496 to R.T.), and the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement no.101005026. The J.U. receives support from the European Union’s Horizon 2020 research and innovation program and EFPIA. J.M.P. has received funding from the T. von Zastrow foundation, the FWF Wittgenstein award (Z 271-B19), the Austrian Academy of Sciences, the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement No. 101005026, and the Canada 150 Research Chairs Program F18-01336, as well as the Canadian Institutes of Health Research COVID-19 grants F20-02343 and F20-02015. This work was further supported by funding from the Austrian National Foundation for Research, Technology, and Development and Research Department of the State of Upper Austria (Y.O.), from the FWF projects W1224 (N.F.K. and L.M.), V584 (Y.O.), P31599 (R.Z.), P30314 (P.H.), I3183 (P.H.), FWFP35166000 (M.K., P.H.), the WWTF grant LS19-029 (P.H., D.C.), the ÖAW fellowship STIP13202002 (L.H.), the European Union’s Horizon research and innovation program (grant no. H2020-MSCA-ITN-2016) under the Marie Skolodowska-Curie grant agreement No. 721874 (P.H. and D.C.), the FWF Schroedinger fellowship J4332-B28 (M.S.).

Austrian Fields of Science 2012

106006 Biophysics
106002 Biochemistry
106022 Microbiology

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https://phaidra.univie.ac.at/o:1671404Licence: CC BY 4.0

Cite this

Zhu, R., Canena, D., Sikora, M., Klausberger, M., Seferovic, H., Mehdipour, A. R., Hain, L., Laurent, E., Monteil, V., Wirnsberger, G., Wieneke, R., Tampé, R., Kienzl, N. F., Mach, L., Mirazimi, A., Oh, Y. J., Penninger, J. M., Hummer, G., & Hinterdorfer, P. (2022). Force-tuned avidity of spike variant-ACE2 interactions viewed on the single-molecule level. Nature Communications, 13(1), Article 7926. https://doi.org/10.1038/s41467-022-35641-3

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title = "Force-tuned avidity of spike variant-ACE2 interactions viewed on the single-molecule level",

abstract = "Recent waves of COVID-19 correlate with the emergence of the Delta and the Omicron variant. We report that the Spike trimer acts as a highly dynamic molecular caliper, thereby forming up to three tight bonds through its RBDs with ACE2 expressed on the cell surface. The Spike of both Delta and Omicron (B.1.1.529) Variant enhance and markedly prolong viral attachment to the host cell receptor ACE2, as opposed to the early Wuhan-1 isolate. Delta Spike shows rapid binding of all three Spike RBDs to three different ACE2 molecules with considerably increased bond lifetime when compared to the reference strain, thereby significantly amplifying avidity. Intriguingly, Omicron (B.1.1.529) Spike displays less multivalent bindings to ACE2 molecules, yet with a ten time longer bond lifetime than Delta. Delta and Omicron (B.1.1.529) Spike variants enhance and prolong viral attachment to the host, which likely not only increases the rate of viral uptake, but also enhances the resistance of the variants against host-cell detachment by shear forces such as airflow, mucus or blood flow. We uncover distinct binding mechanisms and strategies at single-molecule resolution, employed by circulating SARS-CoV-2 variants to enhance infectivity and viral transmission.",

author = "Rong Zhu and Daniel Canena and Mateusz Sikora and Miriam Klausberger and Hannah Seferovic and Mehdipour, \{Ahmad Reza\} and Lisa Hain and Elisabeth Laurent and Vanessa Monteil and Gerald Wirnsberger and Ralph Wieneke and Robert Tamp{\'e} and Kienzl, \{Nikolaus F.\} and Lukas Mach and Ali Mirazimi and Oh, \{Yoo Jin\} and Penninger, \{Josef M.\} and Gerhard Hummer and Peter Hinterdorfer",

note = "Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = dec,

doi = "10.1038/s41467-022-35641-3",

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Zhu, R, Canena, D, Sikora, M, Klausberger, M, Seferovic, H, Mehdipour, AR, Hain, L, Laurent, E, Monteil, V, Wirnsberger, G, Wieneke, R, Tampé, R, Kienzl, NF, Mach, L, Mirazimi, A, Oh, YJ, Penninger, JM, Hummer, G & Hinterdorfer, P 2022, 'Force-tuned avidity of spike variant-ACE2 interactions viewed on the single-molecule level', Nature Communications, vol. 13, no. 1, 7926. https://doi.org/10.1038/s41467-022-35641-3

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AU - Zhu, Rong

AU - Canena, Daniel

AU - Sikora, Mateusz

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AU - Seferovic, Hannah

AU - Mehdipour, Ahmad Reza

AU - Hain, Lisa

AU - Laurent, Elisabeth

AU - Monteil, Vanessa

AU - Wirnsberger, Gerald

AU - Wieneke, Ralph

AU - Tampé, Robert

AU - Kienzl, Nikolaus F.

AU - Mach, Lukas

AU - Mirazimi, Ali

AU - Oh, Yoo Jin

AU - Penninger, Josef M.

AU - Hummer, Gerhard

AU - Hinterdorfer, Peter

PY - 2022/12

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N2 - Recent waves of COVID-19 correlate with the emergence of the Delta and the Omicron variant. We report that the Spike trimer acts as a highly dynamic molecular caliper, thereby forming up to three tight bonds through its RBDs with ACE2 expressed on the cell surface. The Spike of both Delta and Omicron (B.1.1.529) Variant enhance and markedly prolong viral attachment to the host cell receptor ACE2, as opposed to the early Wuhan-1 isolate. Delta Spike shows rapid binding of all three Spike RBDs to three different ACE2 molecules with considerably increased bond lifetime when compared to the reference strain, thereby significantly amplifying avidity. Intriguingly, Omicron (B.1.1.529) Spike displays less multivalent bindings to ACE2 molecules, yet with a ten time longer bond lifetime than Delta. Delta and Omicron (B.1.1.529) Spike variants enhance and prolong viral attachment to the host, which likely not only increases the rate of viral uptake, but also enhances the resistance of the variants against host-cell detachment by shear forces such as airflow, mucus or blood flow. We uncover distinct binding mechanisms and strategies at single-molecule resolution, employed by circulating SARS-CoV-2 variants to enhance infectivity and viral transmission.

AB - Recent waves of COVID-19 correlate with the emergence of the Delta and the Omicron variant. We report that the Spike trimer acts as a highly dynamic molecular caliper, thereby forming up to three tight bonds through its RBDs with ACE2 expressed on the cell surface. The Spike of both Delta and Omicron (B.1.1.529) Variant enhance and markedly prolong viral attachment to the host cell receptor ACE2, as opposed to the early Wuhan-1 isolate. Delta Spike shows rapid binding of all three Spike RBDs to three different ACE2 molecules with considerably increased bond lifetime when compared to the reference strain, thereby significantly amplifying avidity. Intriguingly, Omicron (B.1.1.529) Spike displays less multivalent bindings to ACE2 molecules, yet with a ten time longer bond lifetime than Delta. Delta and Omicron (B.1.1.529) Spike variants enhance and prolong viral attachment to the host, which likely not only increases the rate of viral uptake, but also enhances the resistance of the variants against host-cell detachment by shear forces such as airflow, mucus or blood flow. We uncover distinct binding mechanisms and strategies at single-molecule resolution, employed by circulating SARS-CoV-2 variants to enhance infectivity and viral transmission.

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DO - 10.1038/s41467-022-35641-3

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C2 - 36566234

AN - SCOPUS:85144635885

SN - 2041-1723

VL - 13

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 7926

ER -

Force-tuned avidity of spike variant-ACE2 interactions viewed on the single-molecule level

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Austrian Fields of Science 2012

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Multiscale simulations of cell adhesion receptor clustering

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Force-tuned avidity of spike variant-ACE2 interactions viewed on the single-molecule level

Abstract

Funding

Austrian Fields of Science 2012

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Multiscale simulations of cell adhesion receptor clustering

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