A Computational Approach to Evaluate the Combined Effect of SARS-CoV-2 RBD Mutations and ACE2 Receptor Genetic Variants on Infectivity: The COVID-19 Host-Pathogen Nexus

  1. Dana Ashoor
  2. Noureddine Ben Khalaf
  3. Maryam Marzouq
  4. Hamdi Jarjanazi
  5. Sadok Chlif
  6. M. Dahmani Fathallah

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Abstract

SARS-CoV-2 infectivity is largely determined by the virus Spike protein binding to the ACE2 receptor. Meanwhile, marked infection rate differences were reported between populations and individuals. To understand the disease dynamic, we developed a computational approach to study the implications of both SARS-CoV-2 RBD mutations and ACE2 polymorphism on the stability of the virus-receptor complex. We used the 6LZG PDB RBD/ACE2 3D model, the mCSM platform, the LigPlot+ and PyMol software to analyze the data on SARS-CoV-2 mutations and ACE variants retrieved from GISAID and Ensembl/GnomAD repository. We observed that out of 351 RBD point mutations, 83% destabilizes the complex according to free energy (ΔΔG) differences. We also spotted variations in the patterns of polar and hydrophobic interactions between the mutations occurring in 15 out of 18 contact residues. Similarly, comparison of the effect on the complex stability of different ACE2 variants showed that the pattern of molecular interactions and the complex stability varies also according to ACE2 polymorphism. We infer that it is important to consider both ACE2 variants and circulating SARS-CoV-2 RBD mutations to assess the stability of the virus-receptor association and evaluate infectivity. This approach might offers a good molecular ground to mitigate the virus spreading.

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  1. Version published to 10.3389/fcimb.2021.707194
  2. Version published to 10.1101/2020.10.23.352344v4 on bioRxiv
  3. Version published to 10.1101/2020.10.23.352344v3 on bioRxiv
  4. Version published to 10.1101/2020.10.23.352344v2 on bioRxiv
  5. ScreenIT

    SciScore for 10.1101/2020.10.23.352344: (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
    To identify the amino acids differences in the spike RBD between the new Wuhan strain SARS-CoV-2 and previously known SARS-CoV (NCBI Reference: YP_009825051.1), the sequence of the RBD domain of both viruses was determined using Pfam sequence analysis (https://pfam.xfam.org) of the S full-protein.
    Pfam
    suggested: (Pfam, RRID:SCR_004726)
    SARS-CoV-2 RBD protein sequence was aligned with SARS-CoV RBD protein using Clustal Omega alignment tool (https://www.ebi.ac.uk/Tools/msa/clustalo/).
    Clustal Omega
    suggested: (Clustal Omega, RRID:SCR_001591)
    The structure was cleaned from water and heteroatoms using PyMol software (PyMol Molecular).
    PyMol
    suggested: (PyMOL, RRID:SCR_000305)
    Interacting residues in the generated structures, involving polar and hydrophobic interactions from both receptor and ligand, were determined using LigPlot+ software [32] and PyMol software was used to illustrate the interacting interface in presence of the most destabilizing mutations in the RBD. 2.3. hACE2 variants analysis: The protein sequence for human ACE2 Isoform 1 (hACE2) was downloaded from the Uniprot data bank (https://www.uniprot.org/) (Uniprot ID: Q9BYF1-1) and used as a reference sequence in this study.
    LigPlot+
    suggested: (LigPlot+, RRID:SCR_018249)
    https://www.uniprot.org/
    suggested: (Universal Protein Resource, RRID:SCR_002380)
    We analyzed 231 human ACE2 SNPs causing protein sequence variations collected from the Ensembl dbSNP, GnomAD and UNIPROT databases.
    Ensembl
    suggested: (Ensembl, RRID:SCR_002344)

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

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  6. Version published to 10.1101/2020.10.23.352344v1 on bioRxiv