The inherent flexibility of receptor binding domains in SARS-CoV-2 spike protein
- RIKEN, Japan
- National Institutes of Biomedical Innovation, Health and Nutrition, Japan
- RIKEN Center for Computational Science, Japan
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
Article and author information
Author details
Hisham M Dokainish
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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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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