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Millisecond-scale molecular dynamics simulation of spike RBD structure reveals evolutionary adaption of SARS-CoV-2 to stably bind ACE2

Gard Nelson, Oleksandr Buzko, Aaron Bassett, Patricia Spilman, Kayvan Niazi, Shahrooz Rabizadeh, View ORCID ProfilePatrick Soon-Shiong
doi: https://doi.org/10.1101/2020.12.11.422055
Gard Nelson
1ImmunityBio, LLC. 9920 Jefferson Blvd., Culver City, CA 90232, USA
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  • For correspondence: gard.nelson@immunitybio.com
Oleksandr Buzko
1ImmunityBio, LLC. 9920 Jefferson Blvd., Culver City, CA 90232, USA
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Aaron Bassett
2NantHealth, Inc. 2040 E. Mariposa Ave., El Segundo, CA 90245
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Patricia Spilman
1ImmunityBio, LLC. 9920 Jefferson Blvd., Culver City, CA 90232, USA
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Kayvan Niazi
1ImmunityBio, LLC. 9920 Jefferson Blvd., Culver City, CA 90232, USA
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Shahrooz Rabizadeh
1ImmunityBio, LLC. 9920 Jefferson Blvd., Culver City, CA 90232, USA
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Patrick Soon-Shiong
1ImmunityBio, LLC. 9920 Jefferson Blvd., Culver City, CA 90232, USA
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  • ORCID record for Patrick Soon-Shiong
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Abstract

The Receptor Binding Domain (RBD) of the SARS-CoV-2 surface spike (S) protein interacts with host angiotensin converting enzyme 2 (ACE2) to gain entry to host cells and initiate infection1–3. Detailed, accurate understanding of key interactions between S RBD and ACE2 provides critical information that may be leveraged in the development of strategies for the prevention and treatment of COVID-19. Utilizing the published sequences and cryo-EM structures of both the viral S RBD and ACE24,5, we performed in silico molecular dynamics (MD) simulations of free S RBD and of its interaction with ACE2 over the exceptionally long durations of 2.9 and 2 milliseconds, respectively, to elucidate the nature and relative affinity of S RBD surface residues for the ACE2 binding region. Our findings reveal that free S RBD has assumed an optimized ACE2 binding-ready conformation, incurring little entropic penalty for binding, an evolutionary adaptation that contributes to its high affinity for the receptor6. We further identified high probability molecular binding interactions that inform both vaccine design and therapeutic development, which may include recombinant ACE2-based spike decoys7 and/or allosteric S RBD-ACE2 binding inhibitors8,9 to prevent or arrest infection and thus disease.

Competing Interest Statement

The authors have declared no competing interest.

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 December 12, 2020.
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Millisecond-scale molecular dynamics simulation of spike RBD structure reveals evolutionary adaption of SARS-CoV-2 to stably bind ACE2
Gard Nelson, Oleksandr Buzko, Aaron Bassett, Patricia Spilman, Kayvan Niazi, Shahrooz Rabizadeh, Patrick Soon-Shiong
bioRxiv 2020.12.11.422055; doi: https://doi.org/10.1101/2020.12.11.422055
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Millisecond-scale molecular dynamics simulation of spike RBD structure reveals evolutionary adaption of SARS-CoV-2 to stably bind ACE2
Gard Nelson, Oleksandr Buzko, Aaron Bassett, Patricia Spilman, Kayvan Niazi, Shahrooz Rabizadeh, Patrick Soon-Shiong
bioRxiv 2020.12.11.422055; doi: https://doi.org/10.1101/2020.12.11.422055

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