Elucidation of the interactions between SARS-CoV-2 Spike protein and wild and mutant types of IFITM proteins by in silico methods

  1. Nazli Irmak Giritlioglu
  2. Gizem Koprululu Kucuk

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Abstract

COVID-19 is a viral disease that has been a threat to the whole world since 2019. Although effective vaccines against the disease have been developed, there are still points to be clarified about the mechanism of SARS-CoV-2, which is the causative agent of COVID-19. In this study, we determined the binding energies and the bond types of complexes formed by open (6VYB) and closed (6VXX) forms of the Spike protein of SARS-CoV-2 and wild and mutant forms of IFITM1, IFITM2, and IFITM3 proteins using the molecular docking approach. First, all missense SNPs were found in the NCBI Single Nucleotide Polymorphism database (dbSNP) for IFITM1, IFITM2, and IFITM3 and analyzed with SIFT, PROVEAN, PolyPhen-2, SNAP2, Mutation Assessor, and PANTHER cSNP web-based tools to determine their pathogenicity. When at least four of these analysis tools showed that the SNP had a pathogenic effect on the protein product, this SNP was saved for further analysis. Delta delta G (DDG) and protein stability analysis for amino acid changes were performed in the web-based tools I-Mutant, MUpro, and SAAFEC-SEQ. The structural effect of amino acid change on the protein product was made using the HOPE web-based tool. HawkDock server was used for molecular docking and Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) analysis and binding energies of all complexes were calculated. BIOVIA Discovery Studio program was utilized to visualize the complexes. Hydrogen bonds, salt bridges, and non-bonded contacts between Spike and IFITM protein chains in the complexes were detected with the PDBsum web-based tool. The best binding energy among the 6VYB-IFITM wild protein complexes belong to 6VYB-IFITM1 (-46.16 kcal/mol). Likewise, among the 6VXX-IFITM wild protein complexes, the most negative binding energy belongs to 6VXX-IFITM1 (-52.42 kcal/mol). An interesting result found in the study is the presence of hydrogen bonds between the cytoplasmic domain of the IFITM1 wild protein and the S2 domain of 6VYB. Among the Spike-IFITM mutant protein complexes, the best binding energy belongs to the 6VXX-IFITM2 N63S complex (-50.77 kcal/mol) and the worst binding energy belongs to the 6VXX-IFITM3 S50T complex (4.86 kcal/mol).

The study suggests that IFITM1 protein may act as a receptor for SARS-CoV-2 Spike protein. Assays must be advanced from in silico to in vitro for the determination of the receptor-ligand interactions between IFITM proteins and SARS-CoV-2.

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  1. ScreenIT

    SciScore for 10.1101/2021.09.13.460130: (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
    PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) [24], SNAP2 (https://rostlab.org/services/snap2web/) [25],
    PolyPhen-2
    suggested: None
    http://genetics.bwh.harvard.edu/pph2/
    suggested: (PolyPhen: Polymorphism Phenotyping, RRID:SCR_013189)
    Mutation Assessor (http://mutationassessor.org/r3/) [26, 27], and Protein Analysis Through Evolutionary Relationships (PANTHER) coding SNP (cSNP) (http://www.pantherdb.org/tools/csnpScoreForm.jsp) [28] tools were used for the first analysis to determine the effects of the missense SNPs.
    PANTHER
    suggested: (PANTHER, RRID:SCR_004869)
    http://www.pantherdb.org/tools/csnpScoreForm.jsp
    suggested: (PANTHER Evolutionary analysis of coding SNPs, RRID:SCR_005145)
    SIFT is a program that predicts the functional effect of an amino acid substitution in a particular protein.
    SIFT
    suggested: (SIFT, RRID:SCR_012813)
    The rsIDs of missense SNPs extracted from NCBI dbSNP were pasted into the SIFT4G predictions tool.
    dbSNP
    suggested: (dbSNP, RRID:SCR_002338)
    Amino acid FASTA sequences of IFITM1, IFITM2, and IFITM3 proteins were copied from UniProt (https://www.uniprot.org/) [31] and inserted into the PROVEAN Protein tool with substitutions.
    https://www.uniprot.org/
    suggested: (Universal Protein Resource, RRID:SCR_002380)
    PolyPhen-2 works similarly to PROVEAN.
    PROVEAN
    suggested: (PROVEAN, RRID:SCR_002182)
    Mutation Assessor and PANTHER cSNP tools estimate the effects of the substitutions in the evolutionary base.
    Mutation Assessor
    suggested: (UMD p53 Mutation Database, RRID:SCR_006720)
    Homology modeling of wild and mutant Types of IFITM1, IFITM2, and IFITM3 proteins: Amino acid sequences (FASTA format) of wild-type protein products of IFITM1, IFITM2, and IFITM3 were obtained from UniProt [31].
    UniProt
    suggested: (UniProtKB, RRID:SCR_004426)
    I-TASSER provides the Confidence (C)-score, estimated TM-score, and estimated RMSD value for each model it creates.
    I-TASSER
    suggested: (I-TASSER, RRID:SCR_014627)

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

    Results from scite Reference Check: We found no unreliable references.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  2. Version published to 10.1101/2021.09.13.460130v1 on bioRxiv