Decreased Interfacial Dynamics Caused by the N501Y Mutation in the SARS-CoV-2 S1 Spike:ACE2 Complex

  1. Wesam S. Ahmed
  2. Angelin M. Philip
  3. Kabir H. Biswas

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Abstract

Coronavirus Disease of 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has resulted in a massive health crisis across the globe, with some genetic variants gaining enhanced infectivity and competitive fitness, and thus significantly aggravating the global health concern. In this regard, the recent SARS-CoV-2 alpha, beta, and gamma variants (B.1.1.7, B.1.351, and P.1 lineages, respectively) are of great significance in that they contain several mutations that increase their transmission rates as evident from clinical reports. By the end of March 2021, these variants were accounting for about two-thirds of SARS-CoV-2 variants circulating worldwide. Specifically, the N501Y mutation in the S1 spike receptor binding domain (S1-RBD) of these variants have been reported to increase its affinity for ACE2, although the basis for this is not entirely clear yet. Here, we dissect the mechanism underlying the increased binding affinity of the N501Y mutant for ACE2 using molecular dynamics (MD) simulations of the available ACE2-S1-RBD complex structure (6M0J) and show a prolonged and stable interfacial interaction of the N501Y mutant S1-RBD with ACE2 compared to the wild type S1-RBD. Additionally, we find that the N501Y mutant S1-RBD displays altered dynamics that likely aids in its enhanced interaction with ACE2. By elucidating a mechanistic basis for the increased affinity of the N501Y mutant S1-RBD for ACE2, we believe that the results presented here will aid in developing therapeutic strategies against SARS-CoV-2 including designing of therapeutic agents targeting the ACE2-S1-RBD interaction.

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  1. Version published to 10.3389/fmolb.2022.846996
  2. Version published to 10.1101/2021.01.07.425307v2 on bioRxiv
  3. ScreenIT

    SciScore for 10.1101/2021.01.07.425307: (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

    Software and Algorithms
    SentencesResources
    21] PyMOL (The PyMOL Molecular Graphics System, Version 2.0.0, Schrödinger, LLC; pymol.org) was used to visualize the three-dimensional structure and to generate the N501Y mutant structure using the Mutagenesis tool plugin available in PyMOL.
    PyMOL
    suggested: (PyMOL, RRID:SCR_000305)
    Representative trajectory movies of 50 ns simulations were prepares by compiling 100 trajectory snapshots (2 snapshots/ns) – that were generated utilizing VMD Movie Maker Tool [25] - using the Fiji image analysis software [26] with a frame-rate of 7/s to create 14 s movies.
    Fiji
    suggested: (Fiji, RRID:SCR_002285)
    Data Analysis and Figure Preparation: GraphPad Prism (version 9 for macOS, GraphPad Software, La Jolla California USA; www.graphpad.com), in combination with Microsoft Excel, was used for data analysis and graph preparation.
    GraphPad
    suggested: (GraphPad Prism, RRID:SCR_002798)
    Microsoft Excel
    suggested: (Microsoft Excel, RRID:SCR_016137)
    Figures were assembled using Adobe Illustrator.
    Adobe Illustrator
    suggested: (Adobe Illustrator, RRID:SCR_010279)

    Results from OddPub: Thank you for sharing your 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.

    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: 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.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    About SciScore

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  4. Version published to 10.1101/2021.01.07.425307v1 on bioRxiv