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Elucidation of interactions regulating conformational stability and dynamics of SARS-CoV-2 S-protein.
Mori, Takaharu; Jung, Jaewoon; Kobayashi, Chigusa; Dokainish, Hisham M; Re, Suyong; Sugita, Yuji.
  • Mori T; Theoretical Molecular Science Laboratory, RIKEN Cluster for Pioneering Research, Wako, Japan.
  • Jung J; Theoretical Molecular Science Laboratory, RIKEN Cluster for Pioneering Research, Wako, Japan; Computational Biophysics Research Team, RIKEN Center for Computational Science, Kobe, Japan.
  • Kobayashi C; Computational Biophysics Research Team, RIKEN Center for Computational Science, Kobe, Japan.
  • Dokainish HM; Theoretical Molecular Science Laboratory, RIKEN Cluster for Pioneering Research, Wako, Japan.
  • Re S; Laboratory for Biomolecular Function Simulation, RIKEN Center for Biosystems Dynamics Research, Kobe, Japan; Center for Drug Design Research, National Institutes of Biomedical Innovation, Health, and Nutrition, Osaka, Japan.
  • Sugita Y; Theoretical Molecular Science Laboratory, RIKEN Cluster for Pioneering Research, Wako, Japan; Computational Biophysics Research Team, RIKEN Center for Computational Science, Kobe, Japan; Laboratory for Biomolecular Function Simulation, RIKEN Center for Biosystems Dynamics Research, Kobe, Japan. Elec
Biophys J ; 120(6): 1060-1071, 2021 03 16.
Article in English | MEDLINE | ID: covidwho-1039304
ABSTRACT
The ongoing COVID-19 pandemic caused by the new coronavirus, SARS-CoV-2, calls for urgent developments of vaccines and antiviral drugs. The spike protein of SARS-CoV-2 (S-protein), which consists of trimeric polypeptide chains with glycosylated residues on the surface, triggers the virus entry into a host cell. Extensive structural and functional studies on this protein have rapidly advanced our understanding of the S-protein structure at atomic resolutions, although most of these structural studies overlook the effect of glycans attached to the S-protein on the conformational stability and functional motions between the inactive down and active up forms. Here, we performed all-atom molecular dynamics simulations of both down and up forms of a fully glycosylated S-protein in solution as well as targeted molecular dynamics simulations between them to elucidate key interdomain interactions for stabilizing each form and inducing the large-scale conformational transitions. The residue-level interaction analysis of the simulation trajectories detects distinct amino acid residues and N-glycans as determinants on conformational stability of each form. During the conformational transitions between them, interdomain interactions mediated by glycosylated residues are switched to play key roles on the stabilization of another form. Electrostatic interactions, as well as hydrogen bonds between the three receptor binding domains, work as driving forces to initiate the conformational transitions toward the active form. This study sheds light on the mechanisms underlying conformational stability and functional motions of the S-protein, which are relevant for vaccine and antiviral drug developments.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Molecular Dynamics Simulation / Spike Glycoprotein, Coronavirus Topics: Vaccines Language: English Journal: Biophys J Year: 2021 Document Type: Article Affiliation country: J.bpj.2021.01.012

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Molecular Dynamics Simulation / Spike Glycoprotein, Coronavirus Topics: Vaccines Language: English Journal: Biophys J Year: 2021 Document Type: Article Affiliation country: J.bpj.2021.01.012