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
Share this article
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
  2. Download BibTeX
  3. Download .RIS

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.

Metrics

  • 2,867
    views
  • 350
    downloads
  • 55
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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

Categories and tags

Research organism

Further reading

    1. Epidemiology and Global Health
    2. Medicine
    3. Microbiology and Infectious Disease

    COVID-19: A Collection of Articles

    Edited by Diane M Harper et al.
    Collection

    eLife has published the following articles on SARS-CoV-2 and COVID-19.

    1. Biochemistry and Chemical Biology
    2. Microbiology and Infectious Disease

    On the role of VP3-PI3P interaction in birnavirus endosomal membrane targeting

    Flavia A Zanetti, Ignacio Fernandez ... Laura Ruth Delgui
    Research Article

    Birnaviruses are a group of double-stranded RNA (dsRNA) viruses infecting birds, fish, and insects. Early endosomes (EE) constitute the platform for viral replication. Here, we study the mechanism of birnaviral targeting of EE membranes. Using the Infectious Bursal Disease Virus (IBDV) as a model, we validate that the viral protein 3 (VP3) binds to phosphatidylinositol-3-phosphate (PI3P) present in EE membranes. We identify the domain of VP3 involved in PI3P-binding, named P2 and localized in the core of VP3, and establish the critical role of the arginine at position 200 (R200), conserved among all known birnaviruses. Mutating R200 abolishes viral replication. Moreover, we propose a two-stage modular mechanism for VP3 association with EE. Firstly, the carboxy-terminal region of VP3 adsorbs on the membrane, and then the VP3 core reinforces the membrane engagement by specifically binding PI3P through its P2 domain, additionally promoting PI3P accumulation.

    1. Biochemistry and Chemical Biology
    2. Microbiology and Infectious Disease

    Cellular Energy Production: Mycofactocin and the mycobacterial electron transport chain

    Stephanie M Stuteley, Ghader Bashiri
    Insight

    In the bacterium M. smegmatis, an enzyme called MftG allows the cofactor mycofactocin to transfer electrons released during ethanol metabolism to the electron transport chain.