Mutations in the B.1.1.7 SARS-CoV-2 Spike Protein Reduce Receptor-Binding Affinity and Induce a Flexible Link to the Fusion Peptide

  1. Eileen Socher
  2. Marcus Conrad
  3. Lukas Heger
  4. Friedrich Paulsen
  5. Heinrich Sticht
  6. Friederike Zunke
  7. Philipp Arnold

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Abstract

The B.1.1.7 variant of the SARS-CoV-2 virus shows enhanced infectiousness over the wild type virus, leading to increasing patient numbers in affected areas. Amino acid exchanges within the SARS-CoV-2 spike protein variant of B.1.1.7 affect inter-monomeric contact sites within the trimer (A570D and D614G) as well as the ACE2-receptor interface region (N501Y), which comprises the receptor-binding domain (RBD) of the spike protein. However, the molecular consequences of mutations within B.1.1.7 on spike protein dynamics and stability or ACE2 binding are largely unknown. Here, molecular dynamics simulations comparing SARS-CoV-2 wild type with the B.1.1.7 variant revealed inter-trimeric contact rearrangements, altering the structural flexibility within the spike protein trimer. Furthermore, we found increased flexibility in direct spatial proximity of the fusion peptide due to salt bridge rearrangements induced by the D614G mutation in B.1.1.7. This study also implies a reduced binding affinity for B.1.1.7 with ACE2, as the N501Y mutation restructures the RBD–ACE2 interface, significantly decreasing the linear interaction energy between the RBD and ACE2. Our results demonstrate how mutations found within B.1.1.7 enlarge the flexibility around the fusion peptide and change the RBD–ACE2 interface. We anticipate our findings to be starting points for in depth biochemical and cell biological analyses of B.1.1.7.

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  1. Version published to 10.3390/biomedicines9050525
  2. ScreenIT

    SciScore for 10.1101/2021.04.06.438584: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    NIH rigor criteria are not applicable to paper type.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Generation of the starting structures: To generate starting structures for wild type, wild type with the D614G mutation (wt+D614G) and B.1.1.7 SARS-CoV-2 we used the protein sequence annotated in UniProt (www.uniprot.org) with the identifier P0DTC2 (SARS-CoV-2; wild-type) and changed the sequence in accordance with the reported deletions (del69-70, del144) for the SARS-CoV-2 B.1.1.7 variant.
    UniProt
    suggested: (UniProtKB, RRID:SCR_004426)
    Contacts were evaluated with an in-house Perl script parsing the trajectory using the prior named Amber tools and assigning contacts based on a distance criterion of ≤5 Å between any pair of atoms, as it was done previously41.
    Amber
    suggested: (AMBER, RRID:SCR_016151)
    Statistics and display: Statistical analyses were generated with GraphPad Prism (version 8.0.0 for Windows, GraphPad Software, San Diego, California USA, www.graphpad.com) and statistical tests were applied as indicated below the figure.
    GraphPad Prism
    suggested: (GraphPad Prism, RRID:SCR_002798)
    Plots were generated in GraphPad and Gnuplot (version 4.6).
    GraphPad
    suggested: (GraphPad Prism, RRID:SCR_002798)
    Gnuplot
    suggested: (Gnuplot, RRID:SCR_008619)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: Please consider improving the rainbow (“jet”) colormap(s) used on pages 14, 17, 18, 20, 22, 25, 26, 27 and 28. At least one figure is not accessible to readers with colorblindness and/or is not true to the data, i.e. not perceptually uniform.

    Results from rtransparent:
    • No conflict of interest statement was detected. If there are no conflicts, we encourage authors to explicit state so.
    • No funding statement was detected.
    • No protocol registration statement was detected.

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  3. Version published to 10.1101/2021.04.06.438584v1 on bioRxiv