Coarse-grained molecular simulations of the binding of the SARS-CoV-2 spike protein RBD to the ACE2 receptor

Abstract

Since it was first observed, the COVID-19 pandemic has created a global emergency for national health systems due to millions of confirmed cases and hundreds of thousands of deaths. At a molecular level, the bottleneck for the infection is the binding of the receptor binding domain (RBD) of the viral spike protein to ACE2, an enzyme exposed on human cell membranes. Several experimental structures of the ACE2:RBD complex have been made available, however they offer only a static description of the arrangements of the molecules in either the free or bound states. In order to gain a dynamic description of the binding process that is key to infection, we use molecular simulations with a coarse grained model of the RBD and ACE2. We find that binding occurs in an all-or-none way, without intermediates, and that even in the bound state, the RBD exhibits a considerably dynamic behaviour. From short equilibrium simulations started in the unbound state we provide snapshots that result in a tentative mechanism of binding. Our findings may be important for the development of drug discovery strategies that target the RBD.

SciScore for 10.1101/2020.02.26.964882: (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

Experimental Models: Cell Lines
Sentences	Resources
About 1×104 Vero cells were seeded into a 96-well plate and incubated for 20-24 h at 37 °C.	Vero suggested: None
Vero E6 cells (5×104 cells/well) were pre-treated with the different concentrations of cinanserin for 1 h and the virus was subsequently added (MOI of 0.05) to allow infection for 2 h.	Vero E6 suggested: None
Software and Algorithms
Sentences	Resources
Cloning, protein expression and purification of COVID-19 virus Mpro: The full-length gene encoding COVID-19 virus Mpro (NC_045512) was optimized and synthesized for Escherichia coli expression (Genewiz,	Genewiz suggested: (GENEWIZ, …

SciScore for 10.1101/2020.02.26.964882: (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

Experimental Models: Cell Lines
Sentences	Resources
About 1×104 Vero cells were seeded into a 96-well plate and incubated for 20-24 h at 37 °C.	Vero suggested: None
Vero E6 cells (5×104 cells/well) were pre-treated with the different concentrations of cinanserin for 1 h and the virus was subsequently added (MOI of 0.05) to allow infection for 2 h.	Vero E6 suggested: None
Software and Algorithms
Sentences	Resources
Cloning, protein expression and purification of COVID-19 virus Mpro: The full-length gene encoding COVID-19 virus Mpro (NC_045512) was optimized and synthesized for Escherichia coli expression (Genewiz,	Genewiz suggested: (GENEWIZ, RRID:SCR_003177)
All experimental data was analyzed using GraphPad Prism.	GraphPad Prism suggested: (GraphPad Prism, RRID:SCR_002798)
Mass deconvolution was performed using Agilent MassHunter Qualitative Analysis B.06.00 software with BioConfirm Workflow.	Agilent MassHunter suggested: (Agilent MassHunter Qualitative Analysis, RRID:SCR_019081)
The acquired MS/MS data were analyzed UniProtKB E.coli database (database released on Nov. 11, 2016) containing nsp5 using Protein Discoverer 2.1.	UniProtKB suggested: (UniProtKB, RRID:SCR_004426)

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.

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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Coarse-grained molecular simulations of the binding of the SARS-CoV-2 spike protein RBD to the ACE2 receptor

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