Sterically confined rearrangements of SARS-CoV-2 Spike protein control cell invasion
- Center for Theoretical Biological Physics, Rice University, United States
- Department of Physics and Astronomy, Rice University, United States
- Department of Chemistry, Rice University, United States
- Department of Biosciences, Rice University, United States
- Center for Theoretical Biological Physics, Northeastern University, United States
- Department of Physics, Northeastern University, United States
Figures
Figure 1
Spike-protein-mediated membrane fusion.
(A) The active Spike protein assembly is composed of the subunits S1 (white surface) and S2 (cartoon representation) (Walls et al., 2020), which remain bound through nonbonded interactions. Numerous …
Figure 2
Simulating Spike-protein-mediated membrane fusion. Simulations with an all-atom structure-based model (Whitford et al., 2009; Noel et al., 2016) allow for transitions between prefusion and postfusion configurations to be observed.
(A) Schematic representation of the energetics in the structure-based model. The postfusion configuration was defined as the global potential energy minimum. The pre-cleavage state (green) is …
Figure 3
Glycan-induced caging of the head domain. Glycans impede head rearrangement by introducing a steric cage.
(A) Snapshot from the caged ensemble illustrates the high density of glycans surrounding the head. (B) To define the duration of each caging event (), we measured zhead and rhead (Figure 2D). …
Figure 4
Caging of head allows for extension of HR1 helix.
(A) Distribution of (number of postfusion-specific HR1 contacts) values when glycans are present. Distribution describes the first frame in each simulation for which the head is outside of the …
Figure 5
Glycans promote host capture.
(A) Snapshot of the glycosylated Spike protein with the head domain in a caged configuration (glycans not shown). Caging allows the fusion peptide tails to extend toward and engage the host …
Figure 6
Schematic of fusion mechanism of the Spike protein.
Initial activation of the Spike protein (left) is associated with release of S1, which is triggered by cleavage at the S2’ site and ACE2 receptor binding. When glycans are present (top), HG will …
Appendix 1—figure 1
Definitions of domains within the S2 protein.
(A) Prefusion S2 subunit structure of the Spike protein. (B) Postfusion S2 subunit structure of the Spike protein. (C) Sequence range of the Head Group (HG), Fusion Peptide (FP), Connecting Region …
Appendix 1—figure 2
TM tilt angle distributions.
(A) Distribution of TM tilt angles (defined in SI results section 1.1) sampled during simulations when glycans are present. (B) Distribution of TM tilt angles sampled during simulations when glycans …
Appendix 1—figure 3
Predicted degree of frustration, by residue.
Density of highly frustrated contacts in a 5Å sphere per residue for prefusion (black) and postfusion (red) S2 subunit structures. Dashed line represents the S2’ cleavage site.
Appendix 1—figure 4
HG rotation.
(A-C) Single time trace of zhead, rhead and the HG principal axis polar angle, θ. (D–G) Snapshots of the orientation of HG, relative to the membrane. During the prefusion-to-postfusion transition, …
Appendix 1—figure 5
Probability distribution when glycans are absent.
Distribution calculated from 1000 independent simulations without glycans.
Appendix 1—figure 6
Relative influence of glycans on HR2 and HG.
(A) Structural model with only glycans shown on HG. (B) Structural model with only HR2 glycans present. (C) Distribution of timescales with only HG glycans present. (D) Distribution with only HR2 …
Appendix 1—figure 7
Glycans promote host capture with dissociated TM region.
(A-D) Even in the case where the TM strands are able to dissociate, the presence of the glycans increases the probability that the FPs will capture the host membrane. 1000 transitions were simulated …
Appendix 1—figure 8
Comparison of probability of FP capture with, and without, a host membrane potential.
Probability of capture, calculated from 1000 simulated transitions. (A) Model with no host membrane, using to define capture. (B) Model with host membrane potential as defined in Equation S1, …
Appendix 1—figure 9
Effective potential for TM confinement in a virtual viral membrane.
The flat-bottom region represents the virtual membrane of width nm, this region allows the TM motif to move freely between the planes and , beyond the flat region an energetic penalty is …
Videos
Video 1
This video shows a representative simulation (1 of 1000) of the fully-glycosylated S2 subunit of the SARS-CoV-2 protein as it transitions from the prefusion to the postfusion configuration.
Tables
Appendix 1—table 1
N-glycan listing.
Complete list of N-glycans included in the simulations.
| N706 | aDMan(1→6)[aDMan(1→3)]aDMan(1→6)[aDMan(1→3)] bDMan(1→4)bDGlcNAc(1→4)bDGlcNAc(1→) |
| N717 | aDMan(1→6)[aDMan(1→3)]aDMan(1→6)[aDMan(1→2)aDMan(1→3)] bDMan(1→4)bDGlcNAc(1→4)bDGlcNAc(1→) |
| N801 | aDMan(1→6)[aDMan(1→3)]aDMan(1→6)[aDMan(1→3)] bDMan(1→4)bDGlcNAc(1→4)bDGlcNAc(1→) |
| N1074 | aDMan(1→6)[aDMan(1→3)]aDMan(1→6)[aDMan(1→3)] bDMan(1→4)bDGlcNAc(1→4)bDGlcNAc(1→) |
| N1098 | aDNeu5Ac(2→6)bDGal(1→4)bDGlcNAc(1→2)aDMan(1→3)[aDMan(1→6) [aDMan(1→3)]aDMan(1→6)]bDMan(1→4)bDGlcNAc(1→4)bDGlcNAc(1→) |
| N1134 | bDGlcNAc(1→2)aDMan(1→6)[bDGlcNAc(1→2)aDMan(1→3)]bDMan(1→4) bDGlcNAc(1→4)[aLFuc(1→6)]bDGlcNAc(1→) |
| N1158 | bDGlcNAc(1→2)aDMan(1→6)[bDGlcNAc(1→2)aDMan(1→3)]bDMan(1→4) bDGlcNAc(1→4)bDGlcNAc(1→) |
| N1173 | bDGlcNAc(1→6)[bDGlcNAc(1→2)]aDMan(1→6)[bDGlcNAc(1→4)[bDGlcNAc(1→2)] aDMan(1→3)]bDMan(1→4)bDGlcNAc(1→4)[aLFuc(1→6)]bDGlcNAc(1→) |
| N1198 | aDNeu5Ac(2→6)bDGal(1→4)bDGlcNAc(1→6)[bDGal(1→4)bDGlcNAc(1→2)] aDMan(1→6)[bDGal(1→4)bDGlcNAc(1→4)[bDGal(1→4)bDGlcNAc(1→2)] aDMan(1→3)]bDMan(1→4)bDGlcNAc(1→4)[aLFuc(1→6)]bDGlcNAc(1→) |
Additional files
-
Supplementary file 1
Structural Model of Prefusion Structure.
- https://cdn.elifesciences.org/articles/70362/elife-70362-supp1-v1.pdb
-
Supplementary file 2
Structural Model of Postfusion Structure.
- https://cdn.elifesciences.org/articles/70362/elife-70362-supp2-v1.pdb
-
Transparent reporting form
- https://cdn.elifesciences.org/articles/70362/elife-70362-transrepform-v1.pdf
