Structural basis of Omicron immune evasion: A comparative computational study of Spike protein-Antibody interaction

  1. Darshan Contractor
  2. Christoph Globisch
  3. Shiv Swaroop
  4. Alok Jain

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Abstract

The COVID-19 pandemic has caused more than 424 million infections and 5.9 million deaths so far. The vaccines used against SARS-COV-2 by now have been able to develop some neutralising antibodies in the vaccinated human population and slow down the infection rate. The effectiveness of the vaccines has been challenged by the emergence of the new strains with numerous mutations in the spike (S) protein of SARS-CoV-2. Since S protein is the major immunogenic protein of the virus and also contains Receptor Binding Domain (RBD) that interacts with the human Angiotensin-Converting Enzyme 2 (ACE2) receptors, any mutations in this region should affect the neutralisation potential of the antibodies leading to the immune evasion. Several variants of concern (VOC) of the virus have emerged so far. Among them, the most critical are Delta (B.1.617.2), and recently reported Omicron (B. 1.1.529) which have acquired a lot of mutations in the spike protein. We have mapped those mutations on the modelled RBD and evaluated the binding affinities of various human antibodies with it. Docking and molecular dynamics simulation studies have been used to explore the effect of the mutations on the structure of the RBD and the RBD-antibody interaction. The analysis shows that the mutations mostly at the interface of a nearby region lower the binding affinity of the antibody by ten to forty per cent, with a downfall in the number of interactions formed as a whole and therefore, it implies the generation of immune escape variants. Notable mutations and their effect was characterised by performing various analyses that explain the structural basis of antibody efficacy in Delta and a compromised neutralisation effect for the Omicron variant. Our results pave the way for robust vaccine design that can be effective for many variants.

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Synopsis

The research study utilises comparative docking and MD simulations analyses to illustrate how mutations in delta and omicron variants affect the binding of antibodies to the spike receptor binding domain (RBD) of SARS CoV-2.

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  1. ScreenIT

    SciScore for 10.1101/2022.03.15.484421: (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
    Based on this knowledge, the neutralising antibodies which bind to the distinct epitope sites of the spike RBD were selected - the S23029 (PDB ID: 6NB7) and the CC12.130 (PDB ID: 6XC2) binding the receptor binding site region, the REGN1098731 (PDB ID: 6XDG) and S30932 (PDB ID: 6WPS) attaching at the proteoglycan site44 and the ones binding the CR302228 site (PDB ID: 6ZLR).
    S30932
    suggested: None
    Software and Algorithms
    SentencesResources
    Molecular dynamics (MD) Simulation studies: All molecular dynamics simulations were performed with GROMACS version 2021.447.
    GROMACS
    suggested: (GROMACS, RRID:SCR_014565)
    The initial structures for the Delta and Omicron mutant were obtained by docking the antibody into a representative structure of the RBD, obtained from a MD simulation, with ClusPro 2.0 as discussed above.
    ClusPro
    suggested: (ClusPro, RRID:SCR_018248)

    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: 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.
    • No funding statement was detected.
    • No protocol registration statement was detected.

    Results from scite Reference Check: We found no unreliable references.

    About SciScore

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  2. Version published to 10.1101/2022.03.15.484421v1 on bioRxiv