Sequence of the SARS-CoV-2 spike transmembrane domain makes it inherently dynamic

  1. Sahil Lall
  2. Padmanabhan Balaram
  3. M.K. Mathew
  4. Shachi Gosavi

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Abstract

The homotrimeric SARS-CoV-2 spike protein enables viral infection by mediating the fusion of the viral envelope with the host membrane. The spike protein is anchored to the SARS-CoV-2 envelope by its transmembrane domain (TMD), which is composed of three TM helices, each contributed by one of the protomers of the homotrimeric spike. Although the TMD is important for SARS-CoV-2 viral fusion and is well-conserved across the Coronaviridae family, it is unclear whether it is a passive anchor of the spike or actively promotes viral fusion. Specifically, the nature of the TMD dynamics and how these dynamics couple to the large pre- to post-fusion conformational transition of the spike ectomembrane domains remains unknown. Here, we computationally study the SARS-CoV-2 spike TMD in both homogenous POPC and cholesterol containing membranes to characterize its structure, dynamics, and self-assembly. Different tools identify distinct segments of the spike sequence as its TM helix. Atomistic simulations of a spike protomer segment that includes the superset of the TM helix predictions show that the membrane-embedded TM sequence bobs, tilts and gains and loses helicity at the membrane edges. Coarse-grained multimerization simulations using representative TM helix structures from the atomistic simulations exhibit diverse trimer populations whose architecture depends on the structure of the TM helix protomer. Multiple overlapping and conflicting dimerization interfaces stabilized these trimeric populations. An asymmetric conformation is populated in addition to a symmetric conformation and several in-between trimeric conformations. While the symmetric conformation reflects the symmetry of the resting spike, the asymmetric TMD conformation could promote viral membrane fusion through the stabilization of a fusion intermediate. Together, our simulations demonstrate that the SARS-CoV-2 spike TM anchor sequence is inherently dynamic, trimerization does not abrogate these dynamics and the various observed TMD conformations may enable viral fusion.

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  1. Version published to 10.1101/2021.06.07.447334v2 on bioRxiv
  2. ScreenIT

    SciScore for 10.1101/2021.06.07.447334: (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
    SentencesResources
    The sequence Pro1213-Cys1236 was modelled with ideal α-helical backbone torsion angles and the rest of the amino acids were designed as random coil, using PyMOL (v2.3.3; Schrodinger).
    PyMOL
    suggested: (PyMOL, RRID:SCR_000305)
    All the simulations were performed using GROMACS 4.6.7 (www.gromacs.org) on our high performance computing cluster.
    GROMACS
    suggested: (GROMACS, RRID:SCR_014565)

    Results from OddPub: Thank you for sharing your data.

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    Caveats: There is a dearth of experimental data on the composition of the coronavirus envelope. For our simulations, we used only phosphatidylcholine (POPC) lipid which has a single unsaturation in one of the lipid tails. POPC has been shown to be the most abundant lipid comprising up to 70% of phospholipids in a model coronavirus (59) and also has been used as a model lipid for long. Although common for enveloped viruses like influenza and HIV (76, 77), our POPC and cholesterol ratio is an averaged approximation for the various environments that the transmembrane domain of the SARS-CoV-2 would likely experience. Further, the curvature of the viral envelope could have a bearing on transmembrane conformations but is not studied here. Given the sequence of the TRACS, a tantalizing possibility is the Pro1213 residue sandwiched between the two Trp residues, exists in a cis conformation which was not considered here. Finally, the other domains of the spike protein, not included in the simulations here may influence the equilibrium ensemble of conformations of the transmembrane domain.

    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.

    Results from scite Reference Check: We found no unreliable references.

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  3. Version published to 10.1101/2021.06.07.447334v1 on bioRxiv