In silico screening of TMPRSS2 SNPs that affect its binding with SARS-CoV2 spike protein and directly involved in the interaction affinity changes
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Abstract
In this paper, we used in silico analysis to shed light on the possible interaction between TMPRSS2 and SARS-CoV2 spike (S) protein by examining the role of TMPRSS2 single nucleotide polymorphisms (SNPs) in relation with susceptibility and inter-individual variability of SARS-CoV2 infection. First, we used molecular docking of human TMPRSS2 protein to predict the binding site of TMPRSS2, especially the TMPRSS2 link loops, in order to assess the effect TMPRSS2 SNPs. The latter lead to missense variants on the interaction between TMPRSS2 and SARS-CoV2 S protein. In a second step, we further refine our analysis by performing a structure-function analysis of the complexes using PyMol software, and finally by MD simulations to validate the as-obtained results. Our findings show that 17 SNPs among the 692 natural TMPRSS2 coding variants are in positions to influence the binding of TMPRSS2 with the viral S protein. All of them give more important interaction energy as assessed by docking. Among the 17 SNPs, four missense variants E389A, K392Q, T393S and Q438E lead to “directly increasing” the interaction affinity and 2 missense variants R470I and Y416C cause it “directly decreasing”. The R470I and Y416C present in African and American population, respectively. While the other 4 SNP variants (E389A; K392Q; T393S and Q438E) are present only in the European population, which could link the viral infection susceptibility to demographic, geographic and genetic factors.
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SciScore for 10.1101/2021.09.29.462283: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
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Experimental Models: Organisms/Strains Sentences Resources Molecular docking: AutoDock Vina was used to carry out the molecular docking between S1/S2 domain of SARS-CoV2 spike protein and TMPRSS2 wild type or missense variants. TMPRSS2suggested: RRID:NSRRC_0060)Software and Algorithms Sentences Resources TMPRSS2 polymorphism analysis: SNPs in TMPRSS2, with minor allele frequency (MAF) between 0.01 and 0.5, were extracted from Ensembl genome browser (https://asia.ensembl.org/index.html) (Cunningham et al., 2019), gnomAD (https://gnomad.broadinstitute.org/) (Karczewski et al, 2020), 1000 Genomes … SciScore for 10.1101/2021.09.29.462283: (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
Experimental Models: Organisms/Strains Sentences Resources Molecular docking: AutoDock Vina was used to carry out the molecular docking between S1/S2 domain of SARS-CoV2 spike protein and TMPRSS2 wild type or missense variants. TMPRSS2suggested: RRID:NSRRC_0060)Software and Algorithms Sentences Resources TMPRSS2 polymorphism analysis: SNPs in TMPRSS2, with minor allele frequency (MAF) between 0.01 and 0.5, were extracted from Ensembl genome browser (https://asia.ensembl.org/index.html) (Cunningham et al., 2019), gnomAD (https://gnomad.broadinstitute.org/) (Karczewski et al, 2020), 1000 Genomes (https://www.internationalgenome.org/1000-genomes-browsers/) (Siva, 2008), and NHLBI (https://evs.gs.washington.edu/EVS/) (Auer et al., 2012) databases. Ensembl genome browsersuggested: (Ensembl Genome Browser, RRID:SCR_013367)https://gnomad.broadinstitute.org/suggested: (Genome Aggregation Database, RRID:SCR_014964)https://evs.gs.washington.edu/EVS/suggested: (NHLBI Exome Sequencing Project (ESP, RRID:SCR_012761)The functional impact of allelic variants of TMPRSS2 was predicted using sorting intolerant from tolerant (SIFT) (https://sift.bii.a-star.edu.sg/), which predicts the effects of amino acids substitution on protein structure, the score ranges of 0 to 0.05 are considered as deleterious substitutions (Ng et al., 2003), PolyPhen-2(http://genetics.bwh.harvard.edu/pph2/), is a useful database that predicts the possible consequences of amino acid substitution on functional and structural proteins. SIFTsuggested: (SIFT, RRID:SCR_012813)PolyPhen-2suggested: NoneProtein molecular modelling: When this study was started, the crystal structure of human TMPRSS2 has not been filed in the Protein Data Bank (PDB), therefore, we modelled the structure of human TMPRSS2 employing I-TASSER (Iterative Threading Assembly Refinement), which is a strong predictor of protein 3D structure, aiming to determine by computational calculations the spatial location of every atom in a protein molecule from the amino acid sequence (Zhang, 2008). I-TASSERsuggested: (I-TASSER, RRID:SCR_014627)Identification of TMPRSS2 binding interfaces, selection and characterization of SNPs: Although there is not enough information about the active site and the catalytic site of TMPRSS2, by running a protease conserved domain (CD), TMPRSS2 was analyzed, and all its link loops residues were predicted with PyMOL. PyMOLsuggested: (PyMOL, RRID:SCR_000305)Molecular docking: AutoDock Vina was used to carry out the molecular docking between S1/S2 domain of SARS-CoV2 spike protein and TMPRSS2 wild type or missense variants. AutoDocksuggested: (AutoDock, RRID:SCR_012746)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.
Results from scite Reference Check: We found no unreliable references.
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