Continuous flexibility analysis of SARS-CoV-2 Spike prefusion structures

  1. Roberto Melero
  2. Carlos Oscar S. Sorzano
  3. Brent Foster
  4. José-Luis Vilas
  5. Marta Martínez
  6. Roberto Marabini
  7. Erney Ramírez-Aportela
  8. Ruben Sanchez-Garcia
  9. David Herreros
  10. Laura del Caño
  11. Patricia Losana
  12. Yunior C. Fonseca-Reyna
  13. Pablo Conesa
  14. Daniel Wrapp
  15. Pablo Chacon
  16. Jason S. McLellan
  17. Hemant D. Tagare
  18. Jose-Maria Carazo

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Abstract

With the help of novel processing workflows and algorithms, we have obtained a better understanding of the flexibility and conformational dynamics of the SARS-CoV-2 spike in the prefusion state. We have re-analyzed previous cryo-EM data combining 3D clustering approaches with ways to explore a continuous flexibility space based on 3D Principal Component Analysis. These advanced analyses revealed a concerted motion involving the receptor-binding domain (RBD), N-terminal domain (NTD), and subdomain 1 and 2 (SD1 & SD2) around the previously characterized 1-RBD-up state, which have been modeled as elastic deformations. We show that in this dataset there are not well-defined, stable, spike conformations, but virtually a continuum of states moving in a concerted fashion. We obtained an improved resolution ensemble map with minimum bias, from which we model by flexible fitting the extremes of the change along the direction of maximal variance. Moreover, a high-resolution structure of a recently described biochemically stabilized form of the spike is shown to greatly reduce the dynamics observed for the wild-type spike. Our results provide new detailed avenues to potentially restrain the spike dynamics for structure-based drug and vaccine design and at the same time give a warning of the potential image processing classification instability of these complicated datasets, having a direct impact on the interpretability of the results.

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    SciScore for 10.1101/2020.07.08.191072: (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
    Most of the image processing done in this work has been done using Scipion framework (de la Rosa-Trevín et al., 2016) which is a public domain image processing framework freely available at url http://scipion.i2pc.es.
    Scipion
    suggested: (SCIPION, RRID:SCR_016738)
    The former structure (PDB ID 6VSB) was fitted to the new map and refined using Coot (Emsley et al., 2010) and Phenix real space refine (Afonine et al., 2018).
    Coot
    suggested: (Coot, RRID:SCR_014222)
    Validation metrics were computed to assess the geometry of the new hybrid model and its correlation with the map using Phenix comprehensive validation (cryo-EM), EMRinger algorithm (Barad et al., 2015), Q-score (Pintilie et al., 2020) and FSC-Q (Ramírez-Aportela et al., 2020a).
    Phenix
    suggested: (Phenix, RRID:SCR_014224)

    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: Please consider improving the rainbow (“jet”) colormap(s) used on pages 11, 12, 13, 14 and 22. 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.

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  2. Version published to 10.1101/2020.07.08.191072 on bioRxiv