Improved binding affinity of the Omicron’s spike protein with hACE2 receptor is the key factor behind its increased virulence

  1. Rajender Kumar
  2. N. Arul Murugan
  3. Vaibhav Srivastava

Reviewed by

Read the full article See related articles

Listed in

Log in to save this article

Abstract

The new variant of SARS-CoV-2, Omicron, has been quickly spreading in many countries worldwide. Compared to the original virus, Omicron is characterized by several mutations in its genomic region, including spike protein’s receptor-binding domain (RBD). We have computationally investigated the interaction between RBD of both wild-type and omicron variants with hACE2 receptor using molecular dynamics and MM-GBSA based binding free energy calculations. The mode of the interaction between Omicron’s RBD to the human ACE2 (hACE2) receptor is similar to the original SARS-CoV-2 RBD except for a few key differences. The binding free energy difference shows that the spike protein of Omicron has increased binding affinity for the hACE-2 receptor. The mutated residues in the RBD showed strong interactions with a few amino acid residues of the hACE2. More specifically, strong electrostatic interactions (salt bridges) and hydrogen bonding were observed between R493 and R498 residues of the Omicron RBD with D30/E35 and D38 residues of the hACE2, respectively. Other mutated amino acids in the Omicron RBD, e.g. S496 and H505, also exhibited hydrogen bonding with the hACE2 receptor. The pi-stacking interaction was also observed between tyrosine residues (RBD-Tyr501: hACE2-Tyr41) in the complex, which contributes majorly to binding free energies suggesting this as one of the key interactions stabilizing the complex formation. The structural insights of RBD:hACE2 complex, their binding mode information and residue wise contributions to binding free energy provide insight on the increased transmissibility of Omicron and pave the way to design and optimize novel antiviral agents.

Article activity feed

  1. ScreenIT

    SciScore for 10.1101/2021.12.28.474338: (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
    Sequence analysis and structure modelling: For comparative analysis, sequences of the receptor-binding motif (RBM) from all reported SARS-CoV-2 variants were retrieved from NCBI database using BlastP program.
    NCBI
    suggested: (NCBI, RRID:SCR_006472)
    BlastP
    suggested: (BLASTP, RRID:SCR_001010)
    Further, sequence redundancy was removed at 100% sequence identity, and the remaining representative sequences were aligned using EBI-MUSCLE program (https://www.ebi.ac.uk/Tools/msa/muscle/).
    https://www.ebi.ac.uk/Tools/msa/muscle/
    suggested: (MUSCLE, RRID:SCR_011812)
    For computational modelling, all 15 RBD substitutions G339D, S371L, S373P, S375F, K417N, N440K, G446S, S477N, T478K, E484A, Q493R, G496S, Q498R, N501Y, and Y505H were incorporated into the original resolved crystal structure (PDB ID: 7A91) [17] using the Mutagenesis module of PyMOL software (http://www.pymol.org/pymo) to get the Omicron spike RBD model structure.
    PyMOL
    suggested: (PyMOL, RRID:SCR_000305)
    4.2 MD Simulation and MM-GBSA free energy calculations: Molecular dynamics simulations of the protein complexes, (i) Omicron-RBD:hACE2, and (ii) wt-RBD:hACE2, were carried out using the AMBER 18.0 package [18, 19] where f14SB force field [20] parameters were applied for proteins.
    AMBER
    suggested: (AMBER, RRID:SCR_016151)

    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 10.1101/2021.12.28.474338v1 on bioRxiv