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Review 2: "Binding Profile Assessment of N501Y: a More Infectious Mutation on the Receptor Binding Domain of SARS-CoV-2 Spike Protein"

This preprint uses MD simulations to determine the Spike protein-ACE2 free binding energy and finds the N501Y mutant elicits increased binding affinity. Reviewers find the major claims reliable, but highlight these findings were previously reported by other groups.

Published onMar 15, 2021
Review 2: "Binding Profile Assessment of N501Y: a More Infectious Mutation on the Receptor Binding Domain of SARS-CoV-2 Spike Protein"
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Binding Profile Assessment of N501Y: a More Infectious Mutation on the Receptor Binding Domain of SARS-CoV-2 Spike Protein
Description

<p>Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first reported in December 2019 and has accumulated nearly a hundred million reported infections thereafter. This highly transmissible and pathogenic coronavirus has caused a pandemic of acute respiratory disease, coronavirus disease 2019 (COVID-19), which has caught extensive attention and greatly changed people’s lifestyles all over the world. As an RNA virus, SARS-CoV-2 mutates rapidly as the virus replicates. The world health organization is now closely monitoring the emergence of a new variant, N501Y, on the spike protein. This N501Y variant is found to have higher transmission ability and infectivity, and is believed to be related to the rapid increase of COVID-19 cases in December 2020 in the UK. It was recently reported that the N501Y variants reduce neutralization sensitivity to convalescent sera and monoclonal antibodies. The Tyr mutation at 501 is located at the receptor binding domain (RBD) of the spike protein, the area that directly contacts human ACE2 (hACE2). It’s urgent to figure out the driving force of the new mutant’s enhanced infectivity. Thus, a computational aided binding profile prediction is made to investigate the binding affinity alteration and potential structural change of the N501Y mutant. <a>The resulting structures of N501Y mutant from MD simulations could be used to develop drug inhibitors against hACE2/RBD binding. </a></p>

RR:C19 Evidence Scale rating by reviewer:

  • Strong. The main study claims are very well-justified by the data and analytic methods used. There is little room for doubt that the study produced has very similar results and conclusions as compared with the hypothetical ideal study. The study’s main claims should be considered conclusive and actionable without reservation.

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Review:

The authors of this MS used molecular dynamics simulation to explain the change in the free binding energies between the receptor binding domain of the SARS-CoV-2 and the ACE2. The simulations show an enhanced binding affinities in the N501Y mutant. The results are consistent with a study published before in my lab. However, the author of this study have performed an enhanced sampling by running MD simulations for 200ns starting from different initial states. I found the results convincing and trustable.

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