The inherent flexibility of receptor binding domains in SARS-CoV-2 spike protein

  1. Hisham M Dokainish
  2. Suyong Re
  3. Takaharu Mori
  4. Chigusa Kobayashi
  5. Jaewoon Jung
  6. Yuji Sugita

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Abstract

Spike (S) protein is the primary antigenic target for neutralization and vaccine development for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It decorates the virus surface and undergoes large motions of its receptor binding domains (RBDs) to enter the host cell. Here, we observe Down, one-Up, one-Open, and two-Up-like structures in enhanced molecular dynamics simulations, and characterize the transition pathways via inter-domain interactions. Transient salt-bridges between RBD A and RBD C and the interaction with glycan at N343 B support RBD A motions from Down to one-Up. Reduced interactions between RBD A and RBD B in one-Up induce RBD B motions toward two-Up. The simulations overall agree with cryo-electron microscopy structure distributions and FRET experiments and provide hidden functional structures, namely, intermediates along Down-to-one-Up transition with druggable cryptic pockets as well as one-Open with a maximum exposed RBD. The inherent flexibility of S-protein thus provides essential information for antiviral drug rational design or vaccine development.

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  1. Version published to 10.7554/elife.75720 on eLife
  2. Version published to 10.1101/2021.08.06.455384v2 on bioRxiv
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    SciScore for 10.1101/2021.08.06.455384: (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
    To check the druggability of these pockets, all FDA approved drugs were downloaded from ZINC database46.
    ZINC
    suggested: (Zinc, RRID:SCR_008596)

    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.

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

    About SciScore

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  4. Version published to 10.1101/2021.08.06.455384v1 on bioRxiv