Modelling conformational state dynamics and its role on infection for SARS-CoV-2 Spike protein variants
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Abstract
The SARS-CoV-2 Spike protein needs to be in an open-state conformation to interact with ACE2 to initiate viral entry. We utilise coarse-grained normal mode analysis to model the dynamics of Spike and calculate transition probabilities between states for 17081 variants including experimentally observed variants. Our results correctly model an increase in open-state occupancy for the more infectious D614G via an increase in flexibility of the closed-state and decrease of flexibility of the open-state. We predict the same effect for several mutations on glycine residues (404, 416, 504, 252) as well as residues K417, D467 and N501, including the N501Y mutation recently observed within the B.1.1.7, 501.V2 and P1 strains. This is, to our knowledge, the first use of normal mode analysis to model conformational state transitions and the effect of mutations on such transitions. The specific mutations of Spike identified here may guide future studies to increase our understanding of SARS-CoV-2 infection mechanisms and guide public health in their surveillance efforts.
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SciScore for 10.1101/2020.12.16.423118: (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 Missing residues were reconstructed using template-based loop reconstruction and refinement with Modeller [32]. Modellersuggested: (MODELLER, RRID:SCR_008395)Results from OddPub: Thank you for sharing your code and data.
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:We believe that given the limitations of our coarse-grained model as well as additional phenomena that ultimately affect occupancy, our predictions reflect only a fraction of the myriad of factors contributing to the occupancy. Nonetheless, our predictions correctly …
SciScore for 10.1101/2020.12.16.423118: (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 Missing residues were reconstructed using template-based loop reconstruction and refinement with Modeller [32]. Modellersuggested: (MODELLER, RRID:SCR_008395)Results from OddPub: Thank you for sharing your code and data.
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:We believe that given the limitations of our coarse-grained model as well as additional phenomena that ultimately affect occupancy, our predictions reflect only a fraction of the myriad of factors contributing to the occupancy. Nonetheless, our predictions correctly capture the pattern of relative variations of occupancy observed in the experimental data. To ensure that the calculated correlation is not due to chance, we simulated random sets of occupancies for the 6 sequence variants and calculated simulated correlations for the 110 different combinations of k and γ to determine if the observed correlations represent an actual signal in the data or could be randomly obtained with different values for the parameters k and γ. We observed a marked shift with higher correlations for the data representing our predicted occupancies when compared to the gaussian noise data (Figure S3), suggesting that the predicted occupancies are not due to chance. The computational resources needed for the calculation of occupancies for all 8250 mutations with ΔΔSvib>0 is beyond our current capabilities. We set a threshold of ΔΔSvib>0.3 to select candidates for the calculation of occupancies. This threshold corresponds to 64 mutations (Table 1, in red). Using the parameters k and γ obtained above, we calculated occupancies for these 64 mutants as well as the 20 mutants with lowest ΔΔSvib values (Table 1, in blue). In Figure 10A we show the difference in occupancy between the open and closed state...
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: We did not find any issues relating to colormaps.
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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SciScore for 10.1101/2020.12.16.423118: (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 Missing residues were reconstructed using template-based loop reconstruction and refinement with Modeller [33]. Modellersuggested: (MODELLER, RRID:SCR_008395)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…
SciScore for 10.1101/2020.12.16.423118: (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 Missing residues were reconstructed using template-based loop reconstruction and refinement with Modeller [33]. Modellersuggested: (MODELLER, RRID:SCR_008395)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: We did not find any issues relating to colormaps.
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