Up State of the SARS-COV-2 Spike Homotrimer Favors an Increased Virulence for New Variants

  1. Carolina Corrêa Giron
  2. Aatto Laaksonen
  3. Fernando Luís Barroso da Silva

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Abstract

The COVID-19 pandemic has spread worldwide. However, as soon as the first vaccines—the only scientifically verified and efficient therapeutic option thus far—were released, mutations combined into variants of SARS-CoV-2 that are more transmissible and virulent emerged, raising doubts about their efficiency. This study aims to explain possible molecular mechanisms responsible for the increased transmissibility and the increased rate of hospitalizations related to the new variants. A combination of theoretical methods was employed. Constant-pH Monte Carlo simulations were carried out to quantify the stability of several spike trimeric structures at different conformational states and the free energy of interactions between the receptor-binding domain (RBD) and angiotensin-converting enzyme II (ACE2) for the most worrying variants. Electrostatic epitopes were mapped using the PROCEEDpKa method. These analyses showed that the increased virulence is more likely to be due to the improved stability to the S trimer in the opened state, in which the virus can interact with the cellular receptor, ACE2, rather than due to alterations in the complexation RBD-ACE2, since the difference observed in the free energy values was small (although more attractive in general). Conversely, the South African/Beta variant (B.1.351), compared with the SARS-CoV-2 wild type (wt), is much more stable in the opened state with one or two RBDs in the up position than in the closed state with three RBDs in the down position favoring the infection. Such results contribute to understanding the natural history of disease and indicate possible strategies for developing new therapeutic molecules and adjusting the vaccine doses for higher B-cell antibody production.

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  1. Version published to 10.3389/fmedt.2021.694347
  2. ScreenIT

    SciScore for 10.1101/2021.04.05.438465: (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
    The “UCSF Chimera 1.14” package (72) was employed for all molecular visualizations and representations too.
    Chimera
    suggested: (Chimera, RRID:SCR_002959)
    The linear sequences of the SARS-CoV-1 and 2 S proteins are available in UniProt with the ids P59594 and P0DTC2 for SARS-CoV-1, 2 (wt), and B.1.351, respectively.
    UniProt
    suggested: (UniProtKB, RRID:SCR_004426)
    Alignments of pairwise sequences were obtained by the EMBOSS Needle server (91) with default settings.
    EMBOSS
    suggested: (EMBOSS, RRID:SCR_008493)

    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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  3. Version published to 10.1101/2021.04.05.438465 on bioRxiv