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 () and Peter Hinterdorfer ()
Additional contact information
Rong Zhu: Johannes Kepler University Linz
Daniel Canena: Johannes Kepler University Linz
Mateusz Sikora: Max Planck Institute of Biophysics
Miriam Klausberger: University of Natural Resources and Life Sciences, Vienna
Hannah Seferovic: Johannes Kepler University Linz
Ahmad Reza Mehdipour: Max Planck Institute of Biophysics
Lisa Hain: Johannes Kepler University Linz
Elisabeth Laurent: University of Natural Resources and Life Sciences, Vienna
Vanessa Monteil: Karolinska Institute and Karolinska University Hospital
Gerald Wirnsberger: Apeiron Biologics
Ralph Wieneke: Biocenter, Goethe University Frankfurt
Robert Tampé: Biocenter, Goethe University Frankfurt
Nikolaus F. Kienzl: University of Natural Resources and Life Sciences, Vienna
Lukas Mach: University of Natural Resources and Life Sciences, Vienna
Ali Mirazimi: Karolinska Institute and Karolinska University Hospital
Yoo Jin Oh: Johannes Kepler University Linz
Josef M. Penninger: Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA)
Gerhard Hummer: Max Planck Institute of Biophysics
Peter Hinterdorfer: Johannes Kepler University Linz

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-35641-3

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