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Enhanced sampling protocol to elucidate fusion peptide opening of SARS-CoV-2 spike protein.
Remington, Jacob M; McKay, Kyle T; Ferrell, Jonathon B; Schneebeli, Severin T; Li, Jianing.
  • Remington JM; Department of Chemistry, University of Vermont, Burlington, Vermont.
  • McKay KT; Department of Chemistry, University of Vermont, Burlington, Vermont.
  • Ferrell JB; Department of Chemistry, University of Vermont, Burlington, Vermont.
  • Schneebeli ST; Department of Chemistry, University of Vermont, Burlington, Vermont.
  • Li J; Department of Chemistry, University of Vermont, Burlington, Vermont. Electronic address: jianing.li@uvm.edu.
Biophys J ; 120(14): 2848-2858, 2021 07 20.
Article in English | MEDLINE | ID: covidwho-1607443
ABSTRACT
Large-scale conformational transitions in the spike protein S2 domain are required during host-cell infection of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. Although conventional molecular dynamics simulations have been extensively used to study therapeutic targets of SARS-CoV-2, it is still challenging to gain molecular insight into the key conformational changes because of the size of the spike protein and the long timescale required to capture these transitions. In this work, we have developed an efficient simulation protocol that leverages many short simulations, a dynamic selection algorithm, and Markov state models to interrogate the structural changes of the S2 domain. We discovered that the conformational flexibility of the dynamic region upstream of the fusion peptide in S2 is coupled to the proteolytic cleavage state of the spike protein. These results suggest that opening of the fusion peptide likely occurs on a submicrosecond timescale after cleavage at the S2' site. Building on the structural and dynamical information gained to date about S2 domain dynamics, we provide proof of principle that a small molecule bound to a seam neighboring the fusion peptide can slow the opening of the fusion peptide, leading to a new inhibition strategy for experiments to confirm. In aggregate, these results will aid the development of drug cocktails to inhibit infections caused by SARS-CoV-2 and other coronaviruses.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Spike Glycoprotein, Coronavirus / COVID-19 Limits: Humans Language: English Journal: Biophys J Year: 2021 Document Type: Article

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Spike Glycoprotein, Coronavirus / COVID-19 Limits: Humans Language: English Journal: Biophys J Year: 2021 Document Type: Article