Computational Analysis of Dynamic Allostery and Control in the SARS-CoV-2 Main Protease

  1. Igors Dubanevics
  2. Tom C.B. McLeish

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Abstract

The COVID-19 pandemic caused by the novel coronavirus SARS-CoV-2 has generated a global pandemic and no vaccine or antiviral drugs exist at the moment of writing. An attractive coronavirus drug target is the main protease (M pro , also known as 3CL pro ) because of its vital role in the viral cycle. A significant body of work has been focused on finding inhibitors which bind and block the active site of the main protease, but little has been done to address potential non-competitive inhibition which targets regions beyond the active site, partly because the fundamental biophysics of such allosteric control is still poorly understood. In this work, we construct an Elastic Network Model (ENM) of the SARS-CoV-2 M pro homodimer protein and analyse the dynamics and thermodynamics of the main protease’s ENM. We found a rich and heterogeneous dynamical structure in the correlated motions, including allosterically correlated motions between the homodimeric protease’s active sites. Exhaustive 1-point and 2-point mutation scans of the ENM and their effect on fluctuation free energies confirm previously experimentally identified bioactive residues, but also suggest several new candidate regions that are distant from the active site for control of the protease function. Our results suggest new dynamically-driven control regions as possible candidates for non-competitive inhibiting binding sites in the protease, which may assist the development of current fragmentbased binding screens. The results also provide new insight into the protein physics of fluctuation allostery and its underpinning dynamical structure.

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    SciScore for 10.1101/2020.05.21.105965: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board Statementnot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    No key resources detected.

    Results from OddPub: Thank you for sharing your code and data.

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

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  2. Version published to 10.1101/2020.05.21.105965 on bioRxiv