Structural and computational insights into the SARS-CoV-2 Omicron RBD-ACE2 interaction

  1. Jun Lan
  2. Xinheng He
  3. Yifei Ren
  4. Ziyi Wang
  5. Huan Zhou
  6. Shilong Fan
  7. Chenyou Zhu
  8. Dongsheng Liu
  9. Bin Shao
  10. Tie-Yan Liu
  11. Qisheng Wang
  12. Linqi Zhang
  13. Jiwan Ge
  14. Tong Wang
  15. Xinquan Wang

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Abstract

Since SARS-CoV-2 Omicron variant (B.1.1.529) was reported in November 2021, it has quickly spread to many countries and outcompeted the globally dominant Delta variant in several countries. The Omicron variant contains the largest number of mutations to date, with 32 mutations located at spike (S) glycoprotein, which raised great concern for its enhanced viral fitness and immune escape [1–4] . In this study, we reported the crystal structure of the receptor binding domain (RBD) of Omicron variant S glycoprotein bound to human ACE2 at a resolution of 2.6 Å. Structural comparison, molecular dynamics simulation and binding free energy calculation collectively identified four key mutations (S477N, G496S, Q498R and N501Y) for the enhanced binding of ACE2 by the Omicron RBD compared to the WT RBD. Representative states of the WT and Omicron RBD-ACE2 systems were identified by Markov State Model, which provides a dynamic explanation for the enhanced binding of Omicron RBD. The effects of the mutations in the RBD for antibody recognition were analyzed, especially for the S371L/S373P/S375F substitutions significantly changing the local conformation of the residing loop to deactivate several class IV neutralizing antibodies.

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    SciScore for 10.1101/2022.01.03.474855: (What is this?)

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    Table 1: Rigor

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    Table 2: Resources

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    Structure determination and refinement: The structure was determined using the molecular replacement method with PHASER in the CCP4 suite[27].
    CCP4
    suggested: (CCP4, RRID:SCR_007255)

    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 found bar graphs of continuous data. We recommend replacing bar graphs with more informative graphics, as many different datasets can lead to the same bar graph. The actual data may suggest different conclusions from the summary statistics. For more information, please see Weissgerber et al (2015).

    Results from JetFighter: Please consider improving the rainbow (“jet”) colormap(s) used on page 14. At least one figure is not accessible to readers with colorblindness and/or is not true to the data, i.e. not perceptually uniform.

    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.

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

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  2. Version published to 10.1101/2022.01.03.474855v1 on bioRxiv