Binding mechanism of neutralizing Nanobodies targeting SARS-CoV-2 Spike Glycoprotein
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Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters human cells upon binding of its spike (S) glycoproteins to ACE2 receptors. Several nanobodies neutralize SARS-CoV-2 infection by binding to the receptor-binding domain (RBD) of S protein, but the underlying mechanism is not well understood. Here, we identified an extended network of pairwise interactions between RBD and nanobodies H11-H4, H11-D4, and Ty1 by performing all-atom molecular dynamics (MD) simulations. Simulations of the nanobody-RBD-ACE2 complex revealed that H11-H4 more strongly binds to RBD without overlapping with ACE2 and triggers dissociation of ACE2 due to electrostatic repulsion. In comparison, Ty1 binding results in dissociation of ACE2 from RBD due to an overlap with the ACE2 binding site, whereas H11-D4 binding does not trigger ACE2 dissociation. Mutations in SARS-CoV-2 501Y.V1 and 501.V2 variants resulted in a negligible effect on RBD-ACE2 binding. However, the 501.V2 variant weakened H11-H4 and H11-D4 binding while strengthening Ty1 binding to RBD. Our simulations indicate that all three nanobodies can neutralize 501Y.V1 while Ty1 is more effective against the 501.V2 variant.
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SciScore for 10.1101/2021.04.23.441186: (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 All system preparation steps were performed in VMD.33 Conventional MD Simulations: All MD simulations were performed in NAMD 2.1334 using the CHARMM3635 force field with a time step of 2 fs. NAMDsuggested: (NAMD, RRID:SCR_014894)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 TrialIdent…
SciScore for 10.1101/2021.04.23.441186: (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 All system preparation steps were performed in VMD.33 Conventional MD Simulations: All MD simulations were performed in NAMD 2.1334 using the CHARMM3635 force field with a time step of 2 fs. NAMDsuggested: (NAMD, RRID:SCR_014894)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: 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.
Results from scite Reference Check: We found no unreliable references.
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