Protein structure analysis of the interactions between SARS-CoV-2 spike protein and the human ACE2 receptor: from conformational changes to novel neutralizing antibodies

  1. Ivan Mercurio
  2. Vincenzo Tragni
  3. Francesco Busco
  4. Anna De Grassi
  5. Ciro Leonardo Pierri

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Abstract

The recent severe acute respiratory syndrome, known as Corona Virus Disease 2019 (COVID-19) has spread so much rapidly and severely to induce World Health Organization (WHO) to declare state of emergency over the new coronavirus SARS-CoV-2 pandemic. While several countries have chosen the almost complete lock-down for slowing down SARS-CoV-2 spread, scientific community is called to respond to the devastating outbreak by identifying new tools for diagnosis and treatment of the dangerous COVID-19. With this aim we performed an in silico comparative modeling analysis, which allows to gain new insights about the main conformational changes occurring in the SARS-CoV-2 spike protein, at the level of the receptor binding domain (RBD), along interactions with human cells angiotensin converting enzyme 2 (ACE2) receptor, that favour human cell invasion. Furthermore, our analysis provides i) an ideal pipeline to identify already characterized antibodies that might target SARS-CoV-2 spike RBD, for preventing interactions with the human ACE2, and ii) instructions for building new possible neutralizing antibodies, according to chemical/physical space restraints and complementary determining regions (CDR) mutagenesis of the identified existing antibodies. The proposed antibodies show in silico a high affinity for SARS-CoV-2 spike RBD and can be used as reference antibodies also for building new high affinity antibodies against present and future coronavirus able to invade human cells through interactions of their spike proteins with the human ACE2. More in general, our analysis provides indications for the set-up of the right biological molecular context for investigating spike RBD-ACE2 interactions for the development of new vaccines, diagnosis kits and other treatments based on the usage or the targeting of SARS-CoV-2 spike protein.

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    SciScore for 10.1101/2020.04.17.046185: (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

    Antibodies
    SentencesResources
    All the generated 3D all atom models were energetically minimized by using the Yasara Minimization server (35) 2.3 Antibody 3D modeling and mutagenesis: Starting from the 3D atomic coordinates of the crystallized neutralizing antibodies m396 (2dd8.pdb(44)) and S230 (6nb7.pdb, (45)) directed against the SARS-CoV-1 spike RBD domain, we modelled the interactions of m396 and S230 (6nb7.pdb, (45)) with SARS-CoV-2 spike RBD domain, by superimposing the fragment antigen based (FAB) portions of m396 (2dd8.pdb (44)) and S230 (6nb7.pdb, (45) (both complexed with SARS-CoV-1 RBD) with the SARS-CoV-2 spike RBD domain, complexed with ACE2 (6vw1.pdb), by using PyMOL.
    ACE2
    suggested: None
    Software and Algorithms
    SentencesResources
    The sequences of the retrieved 48 crystallized structures (with reference to those crystallized structures indicated with “Certain” or “High” confidence level in pGenThreader output) were aligned by using ClustalW (31) implemented in the Jalview package (32).
    ClustalW
    suggested: (ClustalW, RRID:SCR_017277)
    Jalview
    suggested: (Jalview, RRID:SCR_006459)
    All the generated 3D all atom models were energetically minimized by using the Yasara Minimization server (35). 2.2. 3D atomic models preparation of SARS-CoV-2 Spike protein in post-fusion conformation and SARS-CoV-2 Spike-ACE2 interactions in pre-fusion conformations: The 3D comparative model of SARS-CoV-2 spike trimer in post-fusion conformation was built by multi-template modeling by using Modeller (36).
    Modeller
    suggested: (MODELLER, RRID:SCR_008395)
    The obtained final models were examined in VMD, PyMOL, and SPDBV according to our protocols (30, 49).
    PyMOL
    suggested: (PyMOL, RRID:SCR_000305)
    The way the FoldX AnalyseComplex operates is by unfolding the selected targets and determining the stability of the remaining molecules and then subtracting the sum of the individual energies from the global energy.
    FoldX
    suggested: (FoldX, RRID:SCR_008522)

    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: Please consider improving the rainbow (“jet”) colormap(s) used on pages 33 and 7. 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.
    • 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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  2. Version published to 10.1101/2020.04.17.046185 on bioRxiv