2021
DOI: 10.1002/1873-3468.14076
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Enhanced binding of the N501Y‐mutated SARS‐CoV‐2 spike protein to the human ACE2 receptor: insights from molecular dynamics simulations

Abstract: Recently, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants (B.1.1.7 and B.1351) have emerged harbouring mutations that make them highly contagious. The N501Y mutation within the receptor-binding domain (RBD) of the spike protein of these SARS-CoV-2 variants may enhance binding to the human angiotensin-converting enzyme 2 (hACE2). However, no molecular explanation for such an enhanced affinity has so far been provided. Here, using all-atom molecular dynamics simulations, we show that Y501 i… Show more

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Cited by 172 publications
(184 citation statements)
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“…The E484K substitution caused a modest but significant increase in affinity as measured by the competition assay employed here but other studies have reported the E484K substitution results in a negligible increase in affinity 26 . Nonetheless our observations are all in agreement with numerous previous reports on the effects of these substitutions on RBD-ACE2 binding 9,12,14,22,2730 . Reduced binding to ACE2 in K417N may result from a decrease in the flexibility of the 468 – 488 region that undergoes a conformational change when bound to ACE2 in the RBD variant containing only the K417N substitution.…”
Section: Discussionsupporting
confidence: 94%
See 1 more Smart Citation
“…The E484K substitution caused a modest but significant increase in affinity as measured by the competition assay employed here but other studies have reported the E484K substitution results in a negligible increase in affinity 26 . Nonetheless our observations are all in agreement with numerous previous reports on the effects of these substitutions on RBD-ACE2 binding 9,12,14,22,2730 . Reduced binding to ACE2 in K417N may result from a decrease in the flexibility of the 468 – 488 region that undergoes a conformational change when bound to ACE2 in the RBD variant containing only the K417N substitution.…”
Section: Discussionsupporting
confidence: 94%
“…The N501Y substitution produced a marked increase in ACE2 affinity consistent with previous reports and the presence of all three variant of concern substitutions exhibited the greatest increase in ACE2 affinity compared to wild-type RBD and bound ACE2 more strongly than the N501Y substitution alone (Figure 4B). These results were consistent with previously reported observations of the effects of variant of concern substitutions on RBD-ACE2 binding 8,9,14,22 .…”
Section: Rbd Variant Of Concern Substitutions Alter Rbd Stability and Ace2 Binding Affinitysupporting
confidence: 94%
“…The role of such mutations have been experimentally addressed, mostly using synthetic viruses generated by targeted mutagenesis. As such the VoC of UK, South African and Northern Brazil origin share the prominent mutation N501Y in the receptor-binding domain (RBD) of S that may favor viral attachment to its cellular receptor hACE2 [10]. Moreover, massive outbreaks in previously heavily affected regions, such as in the Manaus area of Northern Brazil with seropositivity rates of up to 76% prior to disease resurgence, raise the concern of VoC escaping pre-existing immunity [6].…”
Section: Introductionmentioning
confidence: 99%
“…Adaptation of this viral strain in the mouse appeared to be dependent on a critical amino acid change, N501Y (Asn 501 → Tyr), one of the key mutations for the emergence of several SARS-CoV-2 lineages, including B.1.1.7, B.1.351, and P.1 ( Figure 2 , 4 ) ( Goncalves Cabecinhas et al, 2021 ; Gu et al, 2020 ). The molecular dynamics simulations research has shown that the N501Y mutation can increase the overall binding affinity of the RBD with human ACE2 through the hydrophobic interactions between them ( Luan et al, 2021 ). Microscale thermophoresis confirmed that a tyrosine at position 501 enhances ACE2 binding affinity 1.98 times, which in turn plays an essential role in the higher transmission of this virus variant among humans ( Ramanathan et al, 2021 ).…”
Section: Sars-cov-2 Phylogenetic Prediction Of Susceptible Speciesmentioning
confidence: 99%