Capturing a Crucial ‘Disorder-to-Order Transition’ at the Heart of the Coronavirus Molecular Pathology—Triggered by Highly Persistent, Interchangeable Salt-Bridges

  1. Sourav Roy
  2. Prithwi Ghosh
  3. Abhirup Bandyopadhyay
  4. Sankar Basu

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Abstract

The COVID-19 origin debate has greatly been influenced by genome comparison studies of late, revealing the emergence of the Furin-like cleavage site at the S1/S2 junction of the SARS-CoV-2 Spike (FLCSSpike) containing its 681PRRAR685 motif, absent in other related respiratory viruses. Being the rate-limiting (i.e., the slowest) step, the host Furin cleavage is instrumental in the abrupt increase in transmissibility in COVID-19, compared to earlier onsets of respiratory viral diseases. In such a context, the current paper entraps a ‘disorder-to-order transition’ of the FLCSSpike (concomitant to an entropy arrest) upon binding to Furin. The interaction clearly seems to be optimized for a more efficient proteolytic cleavage in SARS-CoV-2. The study further shows the formation of dynamically interchangeable and persistent networks of salt-bridges at the Spike–Furin interface in SARS-CoV-2 involving the three arginines (R682, R683, R685) of the FLCSSpike with several anionic residues (E230, E236, D259, D264, D306) coming from Furin, strategically distributed around its catalytic triad. Multiplicity and structural degeneracy of plausible salt-bridge network archetypes seem to be the other key characteristic features of the Spike–Furin binding in SARS-CoV-2, allowing the system to breathe—a trademark of protein disorder transitions. Interestingly, with respect to the homologous interaction in SARS-CoV (2002/2003) taken as a baseline, the Spike–Furin binding events, generally, in the coronavirus lineage, seems to have preference for ionic bond formation, even with a lesser number of cationic residues at their potentially polybasic FLCSSpike patches. The interaction energies are suggestive of characteristic metastabilities attributed to Spike–Furin interactions, generally to the coronavirus lineage, which appears to be favorable for proteolytic cleavages targeted at flexible protein loops. The current findings not only offer novel mechanistic insights into the coronavirus molecular pathology and evolution, but also add substantially to the existing theories of proteolytic cleavages.

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  1. Version published to 10.3390/vaccines10020301
  2. ScreenIT

    SciScore for 10.1101/2021.12.29.474439: (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
    Missing residues for the baseline structure of SARS-CoV Spike (7AKJ) were also build in a similar fashion using MODELLER, though opting for a much reduced space of conformational sampling (50 runs of ‘automodel’).
    MODELLER
    suggested: (MODELLER, RRID:SCR_008395)
    Blind ab-initio docking in Cluspro 2.0: Subsequent to filling up for the structural voids in the trimeric SARS-CoV-2 Spike (section 2.2), an ensemble docking approach was adapted (using ‘blind docking’ in ClusPro 2.0 [65]
    ClusPro
    suggested: (ClusPro, RRID:SCR_018248)
    Shape Complementarity: For a chosen docked pose which has passed the initial BSA filter (section 2.3.2.1), the shape complementarity [76, 77] at its interface was computed by the shape correlation (Sc) statistic originally proposed, formulated and programmed (as the sc program, part of the CCP4 package [78]) by Lawrence and Colman [76].
    CCP4
    suggested: (CCP4, RRID:SCR_007255)
    All simulations were performed on a local workstation with Gromacs v2021.3 [79] with CUDA acceleration v11.2 powered by an NVIDIA RTX 3080 GPU with 8704 CUDA compute cores resulting in an average output simulation trajectory of ∼ 8.4 ns/day. 2.5.1.
    Gromacs
    suggested: (GROMACS, RRID:SCR_014565)
    Calculation of structure-based equilibrium thermodynamic parameters (ΔH, ΔS, ΔG) for the Spike–Furin binding: As a mean to probe a highly likely event of ‘enthalpy – entropy compensation’ associated implicitly with the the Spike–Furin interaction, structure-based equilibrium thermodynamic parameters (ΔH, ΔS, ΔG) were calculated for the selected representative structure (RR1CoV-2) along its entire MD simulation trajectory (300 ns) using the standalone (C++ with boost library) version (v.4) of FoldX (http://foldxsuite.crg.eu/) [89, 90]
    boost
    suggested: (BOOST, RRID:SCR_013133)
    Along with net free-energy changes (ΔGGbinding/folding) the advanced empirical force field of FoldX also returns a plethora of different favorable or disfavored transition enthalpic as well as entropic energy terms for proteins (folding) and PPI complexes (binding) directly from their high-resolution 3D coordinates (using full atomic description).
    FoldX
    suggested: (FoldX, RRID:SCR_008522)

    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.

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    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 57. 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.
    • No funding statement was detected.
    • No protocol registration statement was detected.

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

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  3. Version published to 10.1101/2021.12.29.474439v1 on bioRxiv