A model for pH coupling of the SARS-CoV-2 spike protein open/closed equilibrium

  1. Jim Warwicker

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Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causative agent of the coronavirus disease 2019 (COVID-19) pandemic, is thought to release its RNA genome at either the cell surface or within endosomes, the balance being dependent on spike protein stability, and the complement of receptors, co-receptors and proteases. To investigate possible mediators of pH-dependence, pKa calculations have been made on a set of structures for spike protein ectodomain and fragments from SARS-CoV-2 and other coronaviruses. Dominating a heat map of the aggregated predictions, three histidine residues in S2 are consistently predicted as destabilizing in pre-fusion (all three) and post-fusion (two of the three) structures. Other predicted features include the more moderate energetics of surface salt–bridge interactions and sidechain–mainchain interactions. Two aspartic acid residues in partially buried salt-bridges (D290–R273 and R355–D398) have pKas that are calculated to be elevated and destabilizing in more open forms of the spike trimer. These aspartic acids are most stabilized in a tightly closed conformation that has been observed when linoleic acid is bound, and which also affects the interactions of D614. The D614G mutation is known to modulate the balance of closed to open trimer. It is suggested that D398 in particular contributes to a pH-dependence of the open/closed equilibrium, potentially coupled to the effects of linoleic acid binding and D614G mutation, and possibly also A570D mutation. These observations are discussed in the context of SARS-CoV-2 infection, mutagenesis studies, and other human coronaviruses.

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  1. Version published to 10.1093/bib/bbab056
  2. Version published to 10.1101/2020.10.31.363176v2 on bioRxiv
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    SciScore for 10.1101/2020.10.31.363176: (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
    Sequence datasets: In order to visualise amino acid sequence conservation alongside electrostatics calculations, a set of 10 S protein sequences was collected, covering the coronavirus family, with UniProt [31] identifiers and coronavirus sub-family: P0DTC2 (SARS-CoV-2, beta), P59594 (SARS-CoV-1, beta), K9N5Q8 (MERS, beta), A3EXG6 (Bat-HKU9, beta), P11224 (MHV-A59, beta), P11223 (Avian-IBV, gamma), Q91AV1 (Porcine-EDV, alpha), P15423 (Human-229E, alpha), P10033 (Feline-IPV, alpha), and B6VDW0 (Bulbul-HKU11, delta).
    UniProt
    suggested: (UniProtKB, RRID:SCR_004426)
    Sequences were aligned with Clustal Omega [32] at the European Bioinformatics Institute [33], and visualised in ESPript [34].
    Clustal Omega
    suggested: (Clustal Omega, RRID:SCR_001591)
    Average predicted ΔpKa is calculated for each ionisable group and placed into a structure file for comparable visualisation (using PyMOL) to that of the web tool (red destabilising, blue stabilising).
    PyMOL
    suggested: (PyMOL, RRID:SCR_000305)

    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 did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: Please consider improving the rainbow (“jet”) colormap(s) used on page 21. 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.
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    • No protocol registration statement was detected.

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  4. Version published to 10.1101/2020.10.31.363176v1 on bioRxiv