Mechanistic Origin of Different Binding Affinities of SARS-CoV and SARS-CoV-2 Spike RBDs to Human ACE2

  1. Zhi-Bi Zhang
  2. Yuan-Ling Xia
  3. Jian-Xin Shen
  4. Wen-Wen Du
  5. Yun-Xin Fu
  6. Shu-Qun Liu

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Abstract

The receptor-binding domain (RBD) of the SARS-CoV-2 spike protein (RBDCoV2) has a higher binding affinity to the human receptor angiotensin-converting enzyme 2 (ACE2) than the SARS-CoV RBD (RBDCoV). Here, we performed molecular dynamics (MD) simulations, binding free energy (BFE) calculations, and interface residue contact network (IRCN) analysis to explore the mechanistic origin of different ACE2-binding affinities of the two RBDs. The results demonstrate that, when compared to the RBDCoV2-ACE2 complex, RBDCoV-ACE2 features enhanced dynamicsand inter-protein positional movements and increased conformational entropy and conformational diversity. Although the inter-protein electrostatic attractive interactions are the primary determinant for the high ACE2-binding affinities of both RBDs, the significantly enhanced electrostatic attractive interactions between ACE2 and RBDCoV2 determine the higher ACE2-binding affinity of RBDCoV2 than of RBDCoV. Comprehensive comparative analyses of the residue BFE components and IRCNs between the two complexes reveal that it is the residue changes at the RBD interface that lead to the overall stronger inter-protein electrostatic attractive force in RBDCoV2-ACE2, which not only tightens the interface packing and suppresses the dynamics of RBDCoV2-ACE2, but also enhances the ACE2-binding affinity of RBDCoV2. Since the RBD residue changes involving gain/loss of the positively/negatively charged residues can greatly enhance the binding affinity, special attention should be paid to the SARS-CoV-2 variants carrying such mutations, particularly those near or at the binding interfaces with the potential to form hydrogen bonds and/or salt bridges with ACE2.

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  1. Version published to 10.3390/cells11081274
  2. ScreenIT

    SciScore for 10.1101/2022.02.05.479221: (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
    The structure-based sequence alignment between RBDCoV and RBDCoV2 was performed using the Dali server (http://ekhidna.biocenter.helsinki.fi/dali/ (accessed on 12 August 2021)) [34] and visualized by ESPript 3.0 (https://espript.ibcp.fr/ESPript/cgi-bin/ESPript.cgi (accessed on 12 August 2021)) [35].
    Dali
    suggested: (Dali Server, RRID:SCR_013433)
    2.2 MD simulations: All MD simulations were performed using the GROMACS 5.1.4 software package [36] with AMBER99SB-ILDN force field [37].
    GROMACS
    suggested: (GROMACS, RRID:SCR_014565)
    For each representative structure of the RBDCoV-ACE2 and RBDCoV2-ACE2 complexes, inter-atomic close contacts, HBs, and SBs were identified using the Chimera ‘Find Contacts’ tool [54] and VMD plugins ‘Hydrogen Bonds’ and ‘Salt Bridge’ [55], respectively.
    Contacts’
    suggested: None
    Finally, the IRCN and interface HB were generated from the 100 representative structures of each complex by Chimera 1.14 [54] and visualized by Cytoscape 3.8.1 [56].
    Cytoscape
    suggested: (Cytoscape, RRID:SCR_003032)

    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: Please consider improving the rainbow (“jet”) colormap(s) used on pages 8 and 7. 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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  3. Version published to 10.1101/2022.02.05.479221v1 on bioRxiv