1. Biochemistry and Chemical Biology
  2. Structural Biology and Molecular Biophysics

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  Is a corresponding author
  1. RIKEN, Japan
  2. National Institutes of Biomedical Innovation, Health and Nutrition, Japan
  3. RIKEN Center for Computational Science, Japan
https://doi.org/10.7554/eLife.75720
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Cite this article
  1. Hisham M Dokainish
  2. Suyong Re
  3. Takaharu Mori
  4. Chigusa Kobayashi
  5. Jaewoon Jung
  6. Yuji Sugita
(2022)
The inherent flexibility of receptor binding domains in SARS-CoV-2 spike protein
eLife 11:e75720.
https://doi.org/10.7554/eLife.75720
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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 RBDA and RBDC and the interaction with glycan at N343B support RBDA motions from Down to one-Up. Reduced interactions between RBDA and RBDB in one-Up induce RBDB motions toward two-Up. The simulations overall agree with cryo-EM 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.

Data availability

The trajectories were computed with GENESIS 2.0 beta, open source program https:// www.r-ccs.riken.jp/labs/cbrt/ and analyzed using GENESIS 1.6.0 analysis tools https://www.r-ccs.riken.jp/labs/cbrt/download/genesis-version-1-6/ Simulation data were deposited at https://covid.molssi.org/ Data of gREST simulations from Down including models and simulation structures are availableHisham M. Dokainish, Suyong Re, Takaharu Mori, Chigusa Kobayashi, Jaewoon Jung, and Yuji Sugita (2021) MolSSI gREST_SSCR Simulation of Trimeric SARS-CoV-2 Spike Protein Starting From Down Conformation. https://doi.org/10.34974/wtbx-0r84Data of gREST_Up simulations including model and simulation structures are availableHisham M. Dokainish, Suyong Re, Takaharu Mori, Chigusa Kobayashi, Jaewoon Jung, and Yuji Sugita (2021) MolSSI gREST_SSCR Simulation of Trimeric SARS-CoV-2 Spike Protein Starting From 1Up Conformation. https://doi.org/10.34974/xn67-xk26

The following data sets were generated

Article and author information

Author details

  1. Hisham M Dokainish

    Theoretical Molecular Science Laboratory, RIKEN, Wako, Japan
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4387-4790

  2. Suyong Re

    Artificial Intelligence Center for Health and Biomedical Research, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan
    Competing interests
    The authors declare that no competing interests exist.

  3. Takaharu Mori

    Theoretical Molecular Science Laboratory, RIKEN, Wako, Saitama, Japan
    Competing interests
    The authors declare that no competing interests exist.

  4. Chigusa Kobayashi

    Computational Biophysics Research Team, RIKEN Center for Computational Science, Kobe, Japan
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5603-4619

  5. Jaewoon Jung

    Computational Biophysics Research Team, RIKEN Center for Computational Science, Kobe, Japan
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2285-4432

  6. Yuji Sugita

    Theoretical Molecular Science Laboratory, RIKEN, Wako, Japan
    For correspondence
    sugita@riken.jp
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9738-9216

Funding

Ministry of Education, Culture, Sports, Science and Technology (FLAGSHIP 2020 project)

  • Yuji Sugita

Ministry of Education, Culture, Sports, Science and Technology (19K06532)

  • Takaharu Mori

RIKEN (Dynamic Structural Biology/Glycolipidologue Initiative/Biology of Intracellular Environments)

  • Yuji Sugita

Ministry of Education, Culture, Sports, Science and Technology (Priority Issue on Post-K computer)

  • Yuji Sugita

Ministry of Education, Culture, Sports, Science and Technology (Program for Promoting Researches on the Supercomputer Fugaku)

  • Yuji Sugita

Ministry of Education, Culture, Sports, Science and Technology (JPMXP1020200101)

  • Yuji Sugita

Ministry of Education, Culture, Sports, Science and Technology (JPMXP1020200201)

  • Yuji Sugita

Ministry of Education, Culture, Sports, Science and Technology (19H05645)

  • Yuji Sugita

Ministry of Education, Culture, Sports, Science and Technology (21H05249)

  • Yuji Sugita

Ministry of Education, Culture, Sports, Science and Technology (20K15737)

  • Hisham M Dokainish

Ministry of Education, Culture, Sports, Science and Technology (19K12229)

  • Suyong Re

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

© 2022, Dokainish et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Hisham M Dokainish
  2. Suyong Re
  3. Takaharu Mori
  4. Chigusa Kobayashi
  5. Jaewoon Jung
  6. Yuji Sugita
(2022)
The inherent flexibility of receptor binding domains in SARS-CoV-2 spike protein
eLife 11:e75720.
https://doi.org/10.7554/eLife.75720

Share this article

https://doi.org/10.7554/eLife.75720

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