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Molecular dynamic simulation reveals E484K mutation enhances spike RBD-ACE2 affinity and the combination of E484K, K417N and N501Y mutations (501Y.V2 variant) induces conformational change greater than N501Y mutant alone, potentially resulting in an escape mutant

Gard Nelson, Oleksandr Buzko, Patricia Spilman, Kayvan Niazi, Shahrooz Rabizadeh, View ORCID ProfilePatrick Soon-Shiong
doi: https://doi.org/10.1101/2021.01.13.426558
Gard Nelson
1ImmunityBio, Inc.
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  • For correspondence: gard.nelson@immunitybio.com
Oleksandr Buzko
1ImmunityBio, Inc.
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Patricia Spilman
1ImmunityBio, Inc.
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Kayvan Niazi
1ImmunityBio, Inc.
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Shahrooz Rabizadeh
1ImmunityBio, Inc.
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Patrick Soon-Shiong
1ImmunityBio, Inc.
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  • ORCID record for Patrick Soon-Shiong
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Abstract

Rapidly spreading SARS-CoV-2 variants present not only an increased threat to human health due to the confirmed greater transmissibility of several of these new strains but, due to conformational changes induced by the mutations, may render first-wave SARS-CoV-2 convalescent sera, vaccine-induced antibodies, or recombinant neutralizing antibodies (nAbs) ineffective. To be able to assess the risk of viral escape from neutralization by first-wave antibodies, we leveraged our capability for Molecular Dynamic (MD) simulation of the spike receptor binding domain (S RBD) and its binding to human angiotensin-converting enzyme 2 (hACE2) to predict alterations in molecular interactions resulting from the presence of the E484K, K417N, and N501Y variants found in the South African 501Y.V2 strain – alone and in combination. We report here the combination of E484K, K417N and N501Y results in the highest degree of conformational alterations of S RBD when bound to hACE2, compared to either E484K or N501Y alone. Both E484K and N501Y increase affinity of S RBD for hACE2 and E484K in particular switches the charge on the flexible loop region of RBD which leads to the formation of novel favorable contacts. Enhanced affinity of S RBD for hACE2 very likely underpins the greater transmissibility conferred by the presence of either E484K or N501Y; while the induction of conformational changes may provide an explanation for evidence that the 501Y.V2 variant, distinguished from the B.1.1.7 UK variant by the presence of E484K, is able to escape neutralization by existing first-wave anti-SARS-CoV-2 antibodies and re-infect COVID-19 convalescent individuals.

Competing Interest Statement

All authors are employee or senior management of ImmunityBio Inc. that is developing a vaccine mentioned in the manuscript

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted January 13, 2021.
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Molecular dynamic simulation reveals E484K mutation enhances spike RBD-ACE2 affinity and the combination of E484K, K417N and N501Y mutations (501Y.V2 variant) induces conformational change greater than N501Y mutant alone, potentially resulting in an esca…
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Molecular dynamic simulation reveals E484K mutation enhances spike RBD-ACE2 affinity and the combination of E484K, K417N and N501Y mutations (501Y.V2 variant) induces conformational change greater than N501Y mutant alone, potentially resulting in an escape mutant
Gard Nelson, Oleksandr Buzko, Patricia Spilman, Kayvan Niazi, Shahrooz Rabizadeh, Patrick Soon-Shiong
bioRxiv 2021.01.13.426558; doi: https://doi.org/10.1101/2021.01.13.426558
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Molecular dynamic simulation reveals E484K mutation enhances spike RBD-ACE2 affinity and the combination of E484K, K417N and N501Y mutations (501Y.V2 variant) induces conformational change greater than N501Y mutant alone, potentially resulting in an escape mutant
Gard Nelson, Oleksandr Buzko, Patricia Spilman, Kayvan Niazi, Shahrooz Rabizadeh, Patrick Soon-Shiong
bioRxiv 2021.01.13.426558; doi: https://doi.org/10.1101/2021.01.13.426558

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