Systemic Effects of Missense Mutations on SARS-CoV-2 Spike Glycoprotein Stability and Receptor Binding Affinity
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Abstract
The spike (S) glycoprotein of SARS-CoV-2 is responsible for the binding to the permissive cells. The receptor-binding domain (RBD) of SARS-CoV-2 S protein directly interacts with the human angiotensin-converting enzyme 2 (ACE2) on the host cell membrane. In this study, we used computational saturation mutagenesis approaches, including structure-based energy calculations and sequence-based pathogenicity predictions, to quantify the systemic effects of missense mutations on SARS-CoV-2 S protein structure and function. A total of 18,354 mutations in S protein were analyzed and we discovered that most of these mutations could destabilize the entire S protein and its RBD. Specifically, residues G431 and S514 in SARS-CoV-2 RBD are important for S protein stability. We analyzed 384 experimentally verified S missense variations and revealed that the dominant pandemic form, D614G, can stabilize the entire S protein. Moreover, many mutations in N-linked glycosylation sites can increase the stability of the S protein. In addition, we investigated 3,705 mutations in SARS-CoV-2 RBD and 11,324 mutations in human ACE2 and found that SARS-CoV-2 neighbor residues G496 and F497 and ACE2 residues D355 and Y41 are critical for the RBD-ACE2 interaction. The findings comprehensively provide potential target sites in the development of drugs and vaccines against COVID-19.
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SciScore for 10.1101/2020.05.21.109835: (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 To study the protein stability of wide type SARS-CoV-2 S, we separated the A chain of 6VYB and introduced P986K and P987V mutations using FoldX (23). FoldXsuggested: (FoldX, RRID:SCR_008522)The PyMOL (http://www.pymol.org/) was used to generate protein structural images and perform structure alignments. PyMOLsuggested: (PyMOL, RRID:SCR_000305)Sequence Analysis and Mutation Pathogenicity: The amino acid sequences of S protein of SARS-CoV-2 (Entry: P0DTC2), SARS-CoV (Entry: P59594) and MERS-CoV (Entry: K9N5Q8) and human ACE2 (Entry: Q9BYF1) were downloaded from UniProt (24). Mutation …SciScore for 10.1101/2020.05.21.109835: (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 To study the protein stability of wide type SARS-CoV-2 S, we separated the A chain of 6VYB and introduced P986K and P987V mutations using FoldX (23). FoldXsuggested: (FoldX, RRID:SCR_008522)The PyMOL (http://www.pymol.org/) was used to generate protein structural images and perform structure alignments. PyMOLsuggested: (PyMOL, RRID:SCR_000305)Sequence Analysis and Mutation Pathogenicity: The amino acid sequences of S protein of SARS-CoV-2 (Entry: P0DTC2), SARS-CoV (Entry: P59594) and MERS-CoV (Entry: K9N5Q8) and human ACE2 (Entry: Q9BYF1) were downloaded from UniProt (24). Mutation Pathogenicitysuggested: NoneThe pairwise sequence alignment was carried out using EMBOSS Water multiple sequence alignment was performed using Clustal Omega and (25). EMBOSSsuggested: (EMBOSS, RRID:SCR_008493)Clustal Omegasuggested: (Clustal Omega, RRID:SCR_001591)R package (https://www.r-project.org/) was used to generate graphs and perform ANOVA test and t test in statistical comparisons of ΔΔG and ΔΔΔG values and SNAP scores. https://www.r-project.org/suggested: (R Project for Statistical Computing, RRID:SCR_001905)SNAPsuggested: (SNAP, RRID:SCR_007936)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 34, 36 and 30. 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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