Probing the Dynamic Structure–Function and Structure-Free Energy Relationships of the Coronavirus Main Protease with Biodynamics Theory

  1. Hongbin Wan
  2. Vibhas Aravamuthan
  3. Robert A. Pearlstein

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Abstract

The SARS-CoV-2 main protease (Mpro) is of major interest as an antiviral drug target. Structure-based virtual screening efforts, fueled by a growing list of apo and inhibitor-bound SARS-CoV/CoV-2 Mpro crystal structures, are underway in many laboratories. However, little is known about the dynamic enzyme mechanism, which is needed to inform both assay development and structure-based inhibitor design. Here, we apply biodynamics theory to characterize the structural dynamics of substrate-induced Mpro activation under nonequilibrium conditions. The catalytic cycle is governed by concerted dynamic structural rearrangements of domain 3 and the m-shaped loop (residues 132–147) on which Cys145 (comprising the thiolate nucleophile and half of the oxyanion hole) and Gly143 (comprising the second half of the oxyanion hole) reside. In particular, we observed the following: (1) Domain 3 undergoes dynamic rigid-body rotation about the domain 2–3 linker, alternately visiting two primary conformational states (denoted as M1pro ↔ M2pro); (2) The Gly143-containing crest of the m-shaped loop undergoes up and down translations caused by conformational changes within the rising stem of the loop (Lys137–Asn142) in response to domain 3 rotation and dimerization (denoted as M1/downpro ↔ 2·M2/uppro) (noting that the Cys145-containing crest is fixed in the up position). We propose that substrates associate to the M1/downpro state, which promotes the M2/downpro state, dimerization (denoted as 2·M2/uppro–substrate), and catalysis. Here, we explore the state transitions of Mpro under nonequilibrium conditions, the mechanisms by which they are powered, and the implications thereof for efficacious inhibition under in vivo conditions.

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  1. Version published to 10.1021/acsptsci.0c00089
  2. ScreenIT

    SciScore for 10.1101/2020.07.19.211185: (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
    2,15,29], Maestro version 2020-1 (Schrodinger, LLC), and PyMol version 2.0 (Schrodinger, LLC). 2QCY, 2Q6G, 6M03, and 6WNP were prepared for WATMD calculations using the pprep tool in Maestro, and the resulting structures were aligned using the structalign tool in Maestro.
    PyMol
    suggested: (PyMOL, RRID:SCR_000305)
    The aligned dimeric structures and their disassembled A and B chains were compared visually using Maestro.
    Maestro
    suggested: (Maestro, RRID:SCR_016748)

    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 pages 33, 34, 35, 66, 67, 59, 61 and 62. 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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  3. Version published to 10.1101/2020.07.19.211185 on bioRxiv