An in-silico based clinical insight on the effect of noticeable CD4 conserved residues of SARS-CoV-2 on the CD4-MHC-II interactions

  1. Selvaa Kumar C
  2. Senthil Arun Kumar
  3. Debjani Dasgupta
  4. Haiyan Wei

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Abstract

The study is aimed to unveil the conserved residues of CD4 in the context of its purposeful interaction with MHC-II at the receptor-binding domain (RBD) of SARS-CoV-2 compared with the envelope (Env) glycoprotein (gp) 120 of HIV-1. The paired CD4 conserved residues, including the matched CD4 interacting MHC-II epitopes of the structural viral protein domains, were chosen for the protein modelling using the SWISS-MODEL online server. Energy minimization and structural validation of the modelled viral protein domains, including the CD4 and MHC-II protein were achieved by CHIMERA and PROCHECK-Ramachandran Plot respectively. Protein-protein docking was performed by the HADDOCK online tool. The binding affinity score was measured using the PRODIGY online server.

As per our docking report, the Env gp120 of HIV-1 with three identical and three conserved residues of CD4 exhibited the highest binding affinity (−13.9 kcal/mol) with MHC-II than the second-highest RBD-S1-SARS-CoV-2 (−12.5 kcal/mol) with three identical and a single conserved residue of CD4. With a noticeable single salt bridge formation identified at the interacting residues Lys305 (of Env gp120-HIV-1) and Glu139 (of MHC-II); the Env gp120 interaction with MHC-II occupied the crucial His144 and Glu194 (salt-bridge) interacting residues of CD4 with the measured buried surface area 2554.8±40.8 Å 2 . Similarly, the RBD-S1-SARS-CoV-2-MHC-II complex showed two salt bridge formations at the residue sites: 1) Arg567 (of SARS-CoV-2)-Glu194 (of MHC-II) 2) 2) Asp568(of SARS-CoV-2)-Arg165 (of MHC-II) with the increased buried surface area of 1910.9±97.1 Å 2 over the SARS-CoV score 1708.2±50.8 Å 2 ; that camouflaged all crucial CD4 interacting residues of MHC-II. In conclusion, the noticeable conserved residues of CD4 at the RBD-S1 sites of SARS-CoV-2 could interrupt the aspired CD4-MHC-II interactions of adaptive immune activation.

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    SciScore for 10.1101/2020.06.19.161802: (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
    Alternatively, the protein sequences of SARS-CoV-1 surface glycoprotein (Accession number:NP_828851.1) , MERS-CoV (Accession number:AYN72346.1), and SARS-CoV-2 (Accession number:QHD43416.1) were downloaded from the NCBI database (https://www.ncbi.nlm.nih.gov/) To identify the SLWDQ conserved motif and its flanking residues, including the active conserved residues of the CD4 co-receptor in the sequence of the above-mentioned virulent viruses; CD4 of the host-Homo sapiens was aligned with each of these protein sequences: 1) Env gp120 of HIV-1 2) SARS-CoV-1 3) SARS-CoV-2 and 4)MERS-CoV using Clustal Omega online server [25].
    https://www.ncbi.nlm.nih.gov/
    suggested: (GENSAT at NCBI - Gene Expression Nervous System Atlas, RRID:SCR_003923)
    Clustal Omega
    suggested: (Clustal Omega, RRID:SCR_001591)
    All structurally modelled protein structures were subjected to energy minimization followed by its structural validation using CHIMERA [27] and ProSa-Web online server [28], respectively.
    CHIMERA
    suggested: (Chimera, RRID:SCR_002959)

    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: 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.
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    • No protocol registration statement was detected.

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  2. Version published to 10.1101/2020.06.19.161802v1 on bioRxiv