Network analysis outlines strengths and weaknesses of emerging SARS-CoV-2 Spike variants

  1. P.D. Manrique
  2. S. Chakraborty
  3. K. Nguyen
  4. R. Mansbach
  5. B. Korber
  6. S. Gnanakaran

Reviewed by

Read the full article

Listed in

Log in to save this article

Abstract

The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has triggered myriad efforts to dissect and understand the structure and dynamics of this complex pathogen. The Spike glycoprotein of SARS-CoV-2 has received special attention as it is the means by which the virus enters the human host cells. The N-terminal domain (NTD) is one of the targeted regions of the Spike protein for therapeutics and neutralizing antibodies against COVID-19. Though its function is not well-understood, the NTD is reported to acquire mutations and deletions that can accelerate the evolutionary adaptation of the virus driving antibody escape. Cellular processes are known to be regulated by complex interactions at the molecular level, which can be characterized by means of a graph representation facilitating the identification of key residues and critical communication pathways within the molecular complex. From extensive all-atom molecular dynamics simulations of the entire Spike for the wild-type and the dominant variant, we derive a weighted graph representation of the protein in two dominant conformations of the receptor-binding-domain; all-down and one-up. We implement graph theory techniques to characterize the relevance of specific residues at facilitating roles of communication and control, while uncovering key implications for fitness and adaptation. We find that many of the reported high-frequency mutations tend to occur away from the critical residues highlighted by our graph theory analysis, implying that these mutations tend to avoid targeting residues that are most critical for protein allosteric communication. We propose that these critical residues could be candidate targets for novel antibody therapeutics. In addition, our analysis provides quantitative insights of the critical role of the NTD and furin cleavage site and their wide-reaching influence over the protein at large. Many of our conclusions are supported by empirical evidence while others point the way towards crucial simulation-guided experiments.

Article activity feed

  1. ScreenIT

    SciScore for 10.1101/2021.09.03.458946: (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
    Atomistic molecular dynamics simulations were performed using the Gromacs software suite with the CHARMM36m force field.
    Gromacs
    suggested: (GROMACS, RRID:SCR_014565)

    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 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 pages 27, 2 and 10. 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.

    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 10.1101/2021.09.03.458946v1 on bioRxiv