Research ArticleVIROLOGY

Atomistic dynamics of a viral infection process: Release of membrane lytic peptides from a non-enveloped virus

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Science Advances  14 Apr 2021:
Vol. 7, no. 16, eabe1761
DOI: 10.1126/sciadv.abe1761
  • Fig. 1 FHV structure.

    (A) T = 3 capsid structure. (B) Asymmetric unit. (C) Interior view of fivefold vertex. The A proteins are blue, and the yellow helices are the γ peptides. All images are generated from PDB ID: 4FTB.

  • Fig. 2 FHV simulation system and titratable residues.

    (A) The simulation system consists of five asymmetric units surrounding a fivefold symmetry axis. The γ peptides associated with the A subunits are retained and can be faintly seen in yellow beneath the fivefold vertex. (B and C) Location of residues that change protonation states in low pH model. The residues consist of D75 (cyan), H215 (yellow), and H334 (orange), which are shown in van der Waal representation. Both a single asymmetric unit (B) and two adjacent asymmetric units (C) are shown to illustrate the location of titrated residues related to neighboring proteins. The H215 residues lie at the center of the asymmetric unit (quasi-threefold symmetric axis), while H334 and D75 lie at the interface between asymmetric units, which is highlighted by the dashed black line. All images are generated externally to the capsid perspective (looking down on capsid) and are from PDB ID: 4FTB.

  • Fig. 3 Structural changes induced by low pH.

    (A) Exposure of solvent-accessible hydrophobic residues at neutral and low pH. (B to E) The pore radius at the fivefold axis is measured for the replicates at both neutral (B) and low pH (D). The structure with the maximum pore radius is shown for neutral (C) and low pH (E) simulations.

  • Fig. 4 pH effects and dynamic couplings.

    (A) Change in SS in the A subunit in going from neutral to low pH. (B and C) The Cα atoms of residues with SS changes greater than 10% are displayed as van der Waal spheres on the A subunit structure. Color scale is from red (largest decrease) to blue (largest increase). Top down (B) and internal (C) views are presented. The black star indicates the location of the fivefold vertex, and the orange dashed line is drawn to illustrate a pathway from H334 to the fivefold vertex. Residues that undergo protonation changes are labeled. (D and E) LMI at neutral (D) and low pH (E). The correlations with less than 0.4 are set to zero to highlight stronger correlations. The blue vertical boxed regions are surrounding the titrating residues (D74, H215, and H334), and the red horizontal box is around residues 178 to 186, which is a loop at the fivefold vertex. (F) The boxed red region in (D) and (E) corresponds to the red loop shown on the pentameric structure.

  • Fig. 5 SMD results using single-peptide CV.

    (A) Work versus Z for the 20 trials at each pH. (B) The final work values are sorted and presented from smallest to largest. The average over the trials is shown at the far right. (C) The maximum force values are presented and ordered from smallest to largest. The average over the trials is shown at the far right. In (B) and (C), the error bars on the average values are the SEM.

  • Fig. 6 Energetic analysis of γ liberation pathways.

    Time series analysis of umbrella sampling data at neutral (A) and low pH (B). The top plot shows the breakdown between equilibration and production data for each window. The middle panel shows the ratio of production to total simulation data, with dashed red line drawn at 20%. The bottom panel shows Neff, with dashed red line drawn at Neff = 20. The y axis is terminated at 200 to highlight lower sampled windows, although many windows have Neff > 200. (C) PMF force at neutral and low pH. Shaded region represents the SD obtained from error analysis using 1000 bootstrapped profiles. (D and E) Structures along the γ liberation pathway at neutral (D) and low pH (E) pathways. Snapshots are the final frame from a given umbrella window.

  • Table 1 List of simulation types and lengths.

    TypepHTrials/windowsSimulation lengthTotal simulation time
    EquilibriumNeutral3500 ns1.50 μs
    EquilibriumLow3500 ns1.50 μs
    SMD: Single-peptide CVNeutral2025–48 ns945 ns
    SMD: Single-peptide CVLow2034–47 ns889 ns
    SMD: Coupled CVNeutral1027–41 ns334 ns
    SMD: Coupled CVLow1022–34 ns284 ns
    Umbrella samplingNeutral69100–322 ns10.67 μs
    Umbrella samplingLow7088–206 ns7.51 μs
    All trajectories23.63 μs

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