The SARS-CoV-2 Spike Variant D614G Favors an Open Conformational State
This article has been Reviewed by the following groups
Discuss this preprint
Start a discussion What are Sciety discussions?Listed in
- Evaluated articles (ScreenIT)
Abstract
The COVID-19 pandemic underwent a rapid transition with the emergence of a SARS-CoV-2 variant that carried the amino acid substitution D614G in the Spike protein that became globally prevalent. The G-form is both more infectious in vitro and associated with increased viral loads in infected people. To gain insight into the mechanism underlying these distinctive characteristics, we employed multiple replicas of microsecond all-atom simulations to probe the molecular-level impact of this substitution on Spike’s closed and open states. The open state enables Spike interactions with its human cellular receptor, ACE2. Here we show that changes in the inter-protomer energetics due to the D614G substitution favor a higher population of infection-capable (open) states. The inter-protomer interactions between S1 and S2 subunits in the open state of the D-form are asymmetric. This asymmetry is resolved in the G-form due to the release of tensile hydrogen bonds resulting in an increased population of open conformations. Thus, the increased infectivity of the G-form is likely due to a higher rate of profitable binding encounters with the host receptor. It is also predicted to be more neutralization sensitive due to enhanced exposure of the receptor binding domain, a key target region for neutralizing antibodies.
Article activity feed
-
SciScore for 10.1101/2020.07.26.219741: (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
Antibodies Sentences Resources This local reorientation could possibly affect FP and even NTD targeting antibodies through extended glycan interactions (Fig. S11). S11suggested: NoneSoftware and Algorithms Sentences Resources All-atom explicit-solvent simulations were performed with the Gromacs v5.1.2 and 2018.3 software packages (9), (10), using the CHARMM36m (11) forcefield and TIP3P water model (12). Gromacssuggested: (GROMACS, RRID:SCR_014565)Following template selection, homology modeling was performed using a Variable Target Function Method of refinement, and 300 steps of template-restrained MD, with MODELLER 9.20 suite (4). MODELLERSciScore for 10.1101/2020.07.26.219741: (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
Antibodies Sentences Resources This local reorientation could possibly affect FP and even NTD targeting antibodies through extended glycan interactions (Fig. S11). S11suggested: NoneSoftware and Algorithms Sentences Resources All-atom explicit-solvent simulations were performed with the Gromacs v5.1.2 and 2018.3 software packages (9), (10), using the CHARMM36m (11) forcefield and TIP3P water model (12). Gromacssuggested: (GROMACS, RRID:SCR_014565)Following template selection, homology modeling was performed using a Variable Target Function Method of refinement, and 300 steps of template-restrained MD, with MODELLER 9.20 suite (4). MODELLERsuggested: (MODELLER, RRID:SCR_008395)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
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 found bar graphs of continuous data. We recommend replacing bar graphs with more informative graphics, as many different datasets can lead to the same bar graph. The actual data may suggest different conclusions from the summary statistics. For more information, please see Weissgerber et al (2015).
Results from JetFighter: Please consider improving the rainbow (“jet”) colormap(s) used on page 13. At least one figure is not accessible to readers with colorblindness and/or is not true to the data, i.e. not perceptually uniform.
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.
-
