D155Y Substitution of SARS-CoV-2 ORF3a Weakens Binding with Caveolin-1

  1. Suchetana Gupta
  2. Ditipriya Mallick
  3. Kumarjeet Banerjee
  4. Shrimon Mukherjee
  5. Soumyadev Sarkar
  6. Sonny TM Lee
  7. Partha Basuchowdhuri
  8. Siddhartha S Jana

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Abstract

The clinical manifestation of the recent pandemic COVID-19, caused by the novel SARS-CoV-2 virus, varies from mild to severe respiratory illness. Although environmental, demographic and co-morbidity factors have an impact on the severity of the disease, contribution of the mutations in each of the viral genes towards the degree of severity needs a deeper understanding for designing a better therapeutic approach against COVID-19. Open Reading Frame-3a (ORF3a) protein has been found to be mutated at several positions. In this work, we have studied the effect of one of the most frequently occurring mutants, D155Y of ORF3a protein, found in Indian COVID-19 patients. Using computational simulations we demonstrated that the substitution at 155th changed the amino acids involved in salt bridge formation, hydrogen-bond occupancy, interactome clusters, and the stability of the protein compared with the other substitutions found in Indian patients. Protein-protein docking using HADDOCK analysis revealed that substitution D155Y weakened the binding affinity of ORF3a with caveolin-1 compared with the other substitutions, suggesting its importance in the overall stability of ORF3a-caveolin-1 complex, which may modulate the virulence property of SARS-CoV-2.

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  1. Version published to 10.1101/2021.03.26.437194v2 on bioRxiv
  2. Version published to 10.1016/j.csbj.2022.01.017
  3. ScreenIT

    SciScore for 10.1101/2021.03.26.437194: (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
    2.1 Bioinformatic Methods: A total of26,656 sequences of ORF3a protein deposited in NCBI database as on Nov 17, 2020 were considered for the bioinformatics analysis.
    NCBI
    suggested: (NCBI, RRID:SCR_006472)
    These structures were aligned using the BLAST algorithm on the NCBI website.
    BLAST
    suggested: (BLASTX, RRID:SCR_001653)
    PROVEAN score of each mutation was determined using PROVEAN web server [24].
    PROVEAN
    suggested: (PROVEAN, RRID:SCR_002182)
    2.3 Molecular dynamics simulation: We performed classical Molecular Dynamics (MD) simulation in AMBER20[28]using AMBER ff14sb force field[29].
    AMBER
    suggested: (AMBER, RRID:SCR_016151)
    The model was then evaluated using the SAVES v5.0 server, where Ramachandran plot and ERRAT analyses were performed[38,39].
    SAVES
    suggested: (SAVES, RRID:SCR_018219)

    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.
    • 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.

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  4. Version published to 10.1101/2021.03.26.437194v1 on bioRxiv