Molecular strategies for antibody binding and escape of SARS-CoV-2 and its mutations

  1. Mohamed Hendy
  2. Samuel Kaufman
  3. Mauricio Ponga

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Abstract

The COVID19 pandemic, caused by SARS-CoV-2, has infected more than 100 million people worldwide. Due to the rapid spreading of SARS-CoV-2 and its impact, it is paramount to find effective treatments against it. Human neutralizing antibodies are an effective method to fight viral infection. However, the recent discovery of new strains that substantially change the S-protein sequence has raised concern about vaccines and antibodies’ effectiveness. Here, we investigated the binding mechanisms between the S-protein and several antibodies. Multiple mutations were included to understand the strategies for antibody escape in new variants. We found that the combination of mutations K417N and E484K produced higher binding energy to ACE2 than the wild type, suggesting higher efficiency to enter host cells. The mutations’ effect depends on the antibody class. While Class I enhances the binding avidity in the presence of N501Y mutation, class II antibodies showed a sharp decline in the binding affinity. Our simulations suggest that Class I antibodies will remain effective against the new strains. In contrast, Class II antibodies will have less affinity to the S-protein, potentially affecting these antibodies’ efficiency.

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  1. ScreenIT

    SciScore for 10.1101/2021.03.04.433970: (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

    Antibodies
    SentencesResources
    Mutations of the RBD: To assess the ability of antibodies to link to mutated S-proteins, we used the recently reported mutation of the S-protein corresponding to MT1: N501Y, MT2: E484K/N501Y, and MT3: K417N/E484K/N501Y.
    MT2
    suggested: None
    E484K/N501Y
    suggested: None
    Software and Algorithms
    SentencesResources
    The configurations and H-bonds were then analyzed with the software Pymol, and the salt bridges with ESBRI (45).
    Pymol
    suggested: (PyMOL, RRID:SCR_000305)

    Results from OddPub: Thank you for sharing your data.

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    Our all-atom MD simulations also have several limitations. For instance, to reduce the computational cost, only part of the S-protein was modeled in this work. Previous studies have shown minor differences in the PMF plot for one single RBD and the full trimeric S-protein (6). However, the complete simulation of the S-protein with glycans can elucidate additional binding mechanisms with antibodies. Additionally, the mutated RBD has been modeled, but cryoEM mutated molecular structures can differ from those used in this work. As far as the authors are concerned, there is not cryoEM of mutated RBD available yet. Differences in the geometry could affect the equilibrium position and, thus, change the energy path. While these limitations can change the actual values found in this work, we argue that the trends will remain the same as the molecular mechanisms will remain mostly unaffected. In conclusion, we have investigated the mechanisms and strategies for antibody binding and escape in SARS-CoV-2. Analysis of the WT and several mutated versions of the RBD and the ACE2 receptor indicates that the binding energy remains at similar levels as the WT for N501Y but increases for mutations K417N and E484K. This observation suggests that strain B.1.351 could have a better dissociation constant and a better effectivity to enter host cells than the WT virus. The effect of the mutations in antibodies’ avidity of these mutations is mainly detrimental, and most antibodies reduce the binding ...

    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: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

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  2. Version published to 10.1101/2021.03.04.433970v1 on bioRxiv