Structural basis of fitness of emerging SARS-COV-2 variants and considerations for screening, testing and surveillance strategy to contain their threat

  1. Sk Ramiz Islam
  2. Debasish Prusty
  3. Soumen Kanti Manna

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Abstract

While emergence of new SAS-COV-2 variants is posing grave challenge to efforts to deal with the COVID-19 pandemic, the structural and molecular basis of their fitness remain poorly understood. We performed in silico analysis of structures of two most frequent SARS-COV-2 mutations, namely, N501Y and E484K, to identify plausible basis of their fitness over the original strain. The analysis suggested that the N501Y mutation is associated with strengthening of intra- as well as intermolecular H-bond in the hACE2 receptor-spike protein complex, which could result in increased affinity and, therefore, higher infectivity. While E484K mutation did not seem to directly affect the binding with hACE2 receptor, it disrupted H-bonding and salt-bridge interaction associated with binding with neutralizing antibody, which could affect chance of re-infection, disease outcome. Survey of several other mutations showing reduction in antibody-mediated neutralization also revealed that similar disruption of H-bonding or salt-bridge or Van der Waals interaction might explain their phenotype. Analysis of GESS database indicated that N501Y, EK484 as well as these other mutations existed since March-April, 2020, might have evolved independently across the world and may keep accumulating, which could affect efficacy of vaccination and antibody-based therapies. Our analysis also indicated that these may spread in spite of current travel restrictions focused on few countries and evolve indigenously warranting intensification of surveillance for emerging mutations among all travellers as well as people in their dwelling zones. Meta-analysis of existing literature showed that repeat testing of travellers, contacts and others under scrutiny 7-11 days after the initial RT-PCR test may significantly help to contain the spread of emerging variants by catching false negative results. In addition, existing evidence calls for development of strain-specific tests, escalated sequencing and broadening the scope of surveillance including in hospitals and animal farms to contain the threat of emerging variants.

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    SciScore for 10.1101/2021.01.28.21250666: (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
    In addition, SNVs of spike protein RBD residues involved in H-bonding or salt bridge (K417, N440, K444, N448, N487, Q493) as well as significant Van der Waals interactions (L452, F453, A475, V483, F486, F490) with residues of neutralizing antibodies as revealed by high resolution crystal structures 27, 33 were also included for analysis.
    K417
    suggested: None
    N440
    suggested: (UC Davis/NIH NeuroMab Facility Cat# N440/21, RRID:AB_2877599)
    K444
    suggested: None
    N448
    suggested: (UC Davis/NIH NeuroMab Facility Cat# N448/50, RRID:AB_2827972)
    N487
    suggested: None
    Q493
    suggested: None
    A475
    suggested: (MBL International Cat# LS-A475, RRID:AB_591867)
    V483
    suggested: None
    F486
    suggested: None
    Software and Algorithms
    SentencesResources
    Effect of individual mutations were examined analyzed by estimating the difference of biding free energies (ΔΔG) using MutaBind2 server (https://lilab.jysw.suda.edu.cn/research/mutabind2/). 28 The PDB file of the mutant complex generated by for the analysis was further used to analyze any significant deviation in the dihedral angles in the Ramachandran Plot using Ramachandran Plot Server (https://zlab.umassmed.edu/bu/rama/) 29 including glycine and proline residues.
    MutaBind2 server
    suggested: None
    Meta-analysis of rate of false negative results in RT-PCR test for SARS-COV-2: A search on the Pubmed with the keywords ‘SARS-COV-2 + RT-PCR + false negative’ was performed to find published and preprint articles.
    Pubmed
    suggested: (PubMed, RRID:SCR_004846)
    Correlation between RTPCR false negative rates and the interval between initial test and reassessment through repeat RTPCR or CT scan were examined using Pearson correlation using GraphPad Prism 7.
    GraphPad Prism
    suggested: (GraphPad Prism, RRID:SCR_002798)

    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.
    • 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.

    About SciScore

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