Impact of emerging mutations on the dynamic properties the SARS-CoV-2 main protease: an in silico investigation

  1. Olivier Sheik Amamuddy
  2. Gennady M. Verkhivker
  3. Özlem Tastan Bishop

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Abstract

The new coronavirus (SARS-CoV-2) is a global threat to world health and its economy. Its main protease (M pro ), which functions as a dimer, cleaves viral precursor proteins in the process of viral maturation. It is a good candidate for drug development owing to its conservation and the absence of a human homolog. An improved understanding of the protein behaviour can accelerate the discovery of effective therapies in order to reduce mortality. 100 ns all-atom molecular dynamics simulations of 50 homology modelled mutant M pro dimers were performed at pH 7 from filtered sequences obtained from the GISAID database. Protease dynamics were analysed using RMSD, RMSF, R g , the averaged betweenness centrality and geometry calculations. Domains from each M pro protomer were found to generally have independent motions, while the dimer-stabilising N-finger region was found to be flexible in most mutants. A mirrored interprotomer pocket was found to be correlated to the catalytic site using compaction dynamics, and can be a potential allosteric target. The high number of titratable amino acids of M pro may indicate an important role of pH on enzyme dynamics, as previously reported for SARS-CoV. Independent coarse-grained Monte Carlo simulations suggest a link between rigidity/mutability and enzymatic function.

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    SciScore for 10.1101/2020.05.29.123190: (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
    PyMOL (version 2.4) [64] was used to remove any non-protein molecule and to reconstitute the biological unit as chains A and B.
    PyMOL
    suggested: (PyMOL, RRID:SCR_000305)
    A local BLAST database was then set up for these sequences using the makeblastdb command available from the BLAST+ application (version 2.8.1) [65].
    BLAST
    suggested: (BLASTX, RRID:SCR_001653)
    BLAST+
    suggested: (Japan Bioinformatics, RRID:SCR_012250)
    Homology modelling, pH adjustment and analysis of residue interactions: PIR-formatted target-template sequence alignment files were generated for each mutant using the BioPython library (Version 1.76) [66] within ad hoc Python scripts for use in MODELLER (version 9.22) [67].
    BioPython
    suggested: (Biopython, RRID:SCR_007173)
    Python
    suggested: (IPython, RRID:SCR_001658)
    MODELLER
    suggested: (MODELLER, RRID:SCR_008395)
    For visualising the overall interactions at given residue positions, the Arpeggio tool [69] was used to programmatically generate the inter-residue interactions, before computing their sums using an in-house Python script.
    Arpeggio
    suggested: (Arpeggio, RRID:SCR_010876)
    Molecular dynamics simulations: All-atom protein MD simulations were run for the protonated dimers using GROMACS (version 2016.1) [71] at the Center for High Performance Computing (CHPC).
    GROMACS
    suggested: (GROMACS, RRID:SCR_014565)
    The generated data was then visualised and analysed using various open source Python libraries, such as matplotlib [72], Seaborn, Pandas [73], NumPy [74], SciPy [75], MDTraj [76] and NGLview [77].
    matplotlib
    suggested: (MatPlotLib, RRID:SCR_008624)
    NumPy
    suggested: (NumPy, RRID:SCR_008633)
    SciPy
    suggested: (SciPy, RRID:SCR_008058)

    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 pages 17 and 15. 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.

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  2. Version published to 10.1101/2020.05.29.123190 on bioRxiv