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Review 1: "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 1: "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:

  • Potentially informative. The main claims made are not strongly justified by the methods and data, but may yield some insight. The results and conclusions of the study may resemble those from the hypothetical ideal study, but there is substantial room for doubt. Decision-makers should consider this evidence only with a thorough understanding of its weaknesses, alongside other evidence and theory. Decision-makers should not consider this actionable, unless the weaknesses are clearly understood and there is other theory and evidence to further support it.

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Review:

The paper addresses an important and current problem but conveniently attempts to ignore a study that already addressed the same problem more than nine months ago.
The importance of the N105 mutants has already been predicted in Critical
Differences between the Binding Features of the Spike Proteins of SARS-CoV‐2 and SARS-CoV, C. Bai and A. Warshel: J. Phys. Chem. B, 124, 5907-12 (2020). This work also generated a binding profile for other mutant. Obviously the present paper must clearly discuss the previous work, clarifying its findings before trying to publish a similar finding.

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