Host cell membrane capture by the SARS CoV-2 spike protein fusion intermediate
This article has been Reviewed by the following groups
Listed in
- Evaluated articles (ScreenIT)
Abstract
Cell entry by SARS-CoV-2 is accomplished by the S2 subunit of the spike S protein on the virion surface by capture of the host cell membrane and fusion with the viral envelope. Capture and fusion require the prefusion S2 to transit to its potent, fusogenic form, the fusion intermediate (FI). However, the FI structure is unknown, detailed computational models of the FI are unavailable, and the mechanisms and timing of membrane capture and fusion are not established. Here, we constructed a full-length model of the CoV-2 FI by extrapolating from known CoV-2 pre- and postfusion structures. In atomistic and coarse-grained molecular dynamics simulations the FI was remarkably flexible and executed large bending and extensional fluctuations due to three hinges in the C-terminal base. Simulations suggested a host cell membrane capture time of ∼ 2 ms. Isolated fusion peptide simulations identified an N-terminal helix that directed and maintained binding to the membrane but grossly underestimated the binding time, showing that the fusion peptide environment is radically altered when attached to its host fusion protein. The large configurational fluctuations of the FI generated a substantial exploration volume that aided capture of the target membrane, and may set the waiting time for fluctuation-triggered refolding of the FI that draws the viral envelope and host cell membrane together for fusion. These results describe the FI as a machinery designed for efficient membrane capture and suggest novel potential drug targets.
Abstract Figure
Article activity feed
-
-
SciScore for 10.1101/2021.04.09.439051: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
Software and Algorithms Sentences Resources The FP and CR were then extracted as a whole from the prefusion structure (PDB: 6XR8) and appended to the HR1 domain in the FI with an arbitrary angle using Pymol. Pymolsuggested: (PyMOL, RRID:SCR_000305)Finally, a complete GP structure was made in the FI using Modeller, by appending the N-terminal portion (residues 686-702) and C-terminal portion (residues 771-815) of the prefusion structure to the solved postfusion GP (residues 703-770). Modellersuggested: (MODELLER, RRID:SCR_008395)Simulations were run in the NPT ensemble at 1 bar and 310 K using GROMACS 2019.656,57. GROMACSsuggested: …SciScore for 10.1101/2021.04.09.439051: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
Software and Algorithms Sentences Resources The FP and CR were then extracted as a whole from the prefusion structure (PDB: 6XR8) and appended to the HR1 domain in the FI with an arbitrary angle using Pymol. Pymolsuggested: (PyMOL, RRID:SCR_000305)Finally, a complete GP structure was made in the FI using Modeller, by appending the N-terminal portion (residues 686-702) and C-terminal portion (residues 771-815) of the prefusion structure to the solved postfusion GP (residues 703-770). Modellersuggested: (MODELLER, RRID:SCR_008395)Simulations were run in the NPT ensemble at 1 bar and 310 K using GROMACS 2019.656,57. GROMACSsuggested: (GROMACS, RRID:SCR_014565)Results from OddPub: Thank you for sharing your code.
Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
-
-