Computational decomposition reveals reshaping of the SARS‐CoV‐2–ACE2 interface among viral variants expressing the N501Y mutation
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Abstract
Variants of concern of the SARS‐CoV‐2 virus with an asparagine‐to‐tyrosine substitution at position 501 (N501Y) in the receptor‐binding domain (RBD) show enhanced infectivity compared to wild‐type, resulting in an altered pandemic situation in affected areas. These SARS‐Cov‐2 variants comprise the two Alpha variants (B.1.1.7, United Kingdom and B.1.1.7 with the additional E484K mutation), the Beta variant (B.1.351, South Africa), and the Gamma variant (P.1, Brazil). Understanding the binding modalities between these viral variants and the host cell receptor ACE2 allows to depict changes, but also common motifs of virus–host cell interaction. The trimeric spike protein expressed at the viral surface contains the RBD that forms the molecular interface with ACE2. All the above‐mentioned variants carry between one and three amino acid exchanges within the interface‐forming region of the RBD, thereby altering the binding interface with ACE2. Using molecular dynamics (MD) simulations and decomposition of intermolecular contacts between the RBD and ACE2, we identified phenylalanine 486, glutamine 498, threonine 500, and tyrosine 505 as important interface‐forming residues across viral variants. However, especially the N501Y exchange increased contact formation for this residue and also induced some local conformational changes. Comparing here, the in silico generated B.1.1.7 RBD–ACE2 complex with the now available experimentally solved structure reveals very similar behavior during MD simulation. We demonstrate, how computational methods can help to identify differences in conformation as well as contact formation for newly emerging viral variants. Altogether, we provide extensive data on all N501Y expressing SARS‐CoV‐2 variants of concern with respect to their interaction with ACE2 and how this induces reshaping of the RBD–ACE2 interface.
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SciScore for 10.1101/2021.05.28.446149: (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 Sentences Resources Trajectory analysis (analysis of root-mean-square fluctuations (RMSF), analysis of contacts (always with distance criterion of ≤5 Å between any pair of atoms; total fraction of contacts for residue pairs), measurement of interatomic distances, calculation of linear interaction energy (electrostatic and van der Waals interactions) was performed using the Amber tool cpptraj (37). Ambersuggested: (AMBER, RRID:SCR_016151)Statistics and display: Statistical analyses were performed with GraphPad Prism (version 8.0.0 for Windows, GraphPad Software, San Diego, California USA, www.graphpad.com) and … SciScore for 10.1101/2021.05.28.446149: (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 Sentences Resources Trajectory analysis (analysis of root-mean-square fluctuations (RMSF), analysis of contacts (always with distance criterion of ≤5 Å between any pair of atoms; total fraction of contacts for residue pairs), measurement of interatomic distances, calculation of linear interaction energy (electrostatic and van der Waals interactions) was performed using the Amber tool cpptraj (37). Ambersuggested: (AMBER, RRID:SCR_016151)Statistics and display: Statistical analyses were performed with GraphPad Prism (version 8.0.0 for Windows, GraphPad Software, San Diego, California USA, www.graphpad.com) and statistical tests were applied as indicated below the figure. GraphPad Prismsuggested: (GraphPad Prism, RRID:SCR_002798)Plots were created in GraphPad and Gnuplot (version 5.2). GraphPadsuggested: (GraphPad Prism, RRID:SCR_002798)Gnuplotsuggested: (Gnuplot, RRID:SCR_008619)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 8 and 16. 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.
- No funding statement was detected.
- No protocol registration statement was detected.
Results from scite Reference Check: We found no unreliable references.
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