Effects of common mutations in the SARS-CoV-2 Spike RBD and its ligand the human ACE2 receptor on binding affinity and kinetics

  1. Michael I Barton
  2. Stuart A MacGowan
  3. Mikhail A Kutuzov
  4. Omer Dushek
  5. Geoffrey J Barton  Is a corresponding author
  6. P Anton van der Merwe  Is a corresponding author
  1. University of Oxford, United Kingdom
  2. University of Dundee, United Kingdom

Abstract

The interaction between the SARS-CoV-2 virus Spike protein receptor binding domain (RBD) and the ACE2 cell surface protein is required for viral infection of cells. Mutations in the RBD are present in SARS-CoV-2 variants of concern that have emerged independently worldwide. For example, the B.1.1.7 lineage has a mutation (N501Y) in its Spike RBD that enhances binding to ACE2. There are also ACE2 alleles in humans with mutations in the RBD binding site. Here we perform a detailed affinity and kinetics analysis of the effect of five common RBD mutations (K417N, K417T, N501Y, E484K and S477N) and two common ACE2 mutations (S19P and K26R) on the RBD/ACE2 interaction. We analysed the effects of individual RBD mutations, and combinations found in new SARS-CoV-2 Alpha (B.1.1.7), Beta (B.1.351) and Gamma (P1) variants. Most of these mutations increased the affinity of the RBD/ACE2 interaction. The exceptions were mutations K417N/T, which decreased the affinity. Taken together with other studies, our results suggest that the N501Y and S477N mutations enhance transmission primarily by enhancing binding, the K417N/T mutations facilitate immune escape, and the E484K mutation enhances binding and immune escape.

Data availability

All data generated and analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Michael I Barton

    Sir William Dunn School, University of Oxford, Oxford, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9263-6481
  2. Stuart A MacGowan

    School of Life Sciences, University of Dundee, Dundee, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4233-5071
  3. Mikhail A Kutuzov

    Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3386-4350
  4. Omer Dushek

    Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5847-5226
  5. Geoffrey J Barton

    School of Life Sciences, University of Dundee, Dundee, United Kingdom
    For correspondence
    g.j.barton@dundee.ac.uk
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9014-5355
  6. P Anton van der Merwe

    Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom
    For correspondence
    anton.vandermerwe@path.ox.ac.uk
    Competing interests
    P Anton van der Merwe, Own shares in BioNTech SE.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9902-6590

Funding

Wellcome Trust (207537/Z/17/Z828)

  • Mikhail A Kutuzov
  • Omer Dushek

Biotechnology and Biological Sciences Research Council (BB/J019364/1)

  • Stuart A MacGowan
  • Geoffrey J Barton

Biotechnology and Biological Sciences Research Council (BB/R014752/1)

  • Stuart A MacGowan
  • Geoffrey J Barton

Wellcome Trust (101651/Z/13/Z).)

  • Stuart A MacGowan
  • Geoffrey J Barton

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Ron AM Fouchier, Erasmus Medical Center, Netherlands

Publication history

  1. Preprint posted: May 18, 2021 (view preprint)
  2. Received: May 25, 2021
  3. Accepted: August 20, 2021
  4. Accepted Manuscript published: August 26, 2021 (version 1)
  5. Accepted Manuscript updated: September 7, 2021 (version 2)
  6. Version of Record published: September 29, 2021 (version 3)

Copyright

© 2021, Barton et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Michael I Barton
  2. Stuart A MacGowan
  3. Mikhail A Kutuzov
  4. Omer Dushek
  5. Geoffrey J Barton
  6. P Anton van der Merwe
(2021)
Effects of common mutations in the SARS-CoV-2 Spike RBD and its ligand the human ACE2 receptor on binding affinity and kinetics
eLife 10:e70658.
https://doi.org/10.7554/eLife.70658
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