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Biophysical characterization of the SARS-CoV-2 spike protein binding with the ACE2 receptor and implications for infectivity

View ORCID ProfileRatul Chowdhury, Costas D. Maranas
doi: https://doi.org/10.1101/2020.03.30.015891
Ratul Chowdhury
1Department of Chemical Engineering, The Pennsylvania State University, University Park. PA 16802
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Costas D. Maranas
1Department of Chemical Engineering, The Pennsylvania State University, University Park. PA 16802
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  • For correspondence: costas@psu.edu
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Abstract

SARS-CoV-2 is a novel highly virulent pathogen which gains entry to human cells by binding with the cell surface receptor – angiotensin converting enzyme (ACE2). We computationally contrasted the binding interactions between human ACE2 and coronavirus spike protein receptor binding domain (RBD) of the 2002 epidemic-causing SARS-CoV-1, SARS-CoV-2, and bat coronavirus RaTG13 using the Rosetta energy function. We find that the RBD of the spike protein of SARS-CoV-2 is highly optimized to achieve very strong binding with human ACE2 (hACE2) which is consistent with its enhanced infectivity. SARS-CoV-2 forms the most stable complex with hACE2 compared to SARS-CoV-1 (23% less stable) or RaTG13 (11% less stable) while occupying the greatest number of residues in the ATR1 binding site. Notably, the SARS-CoV-2 RBD out-competes the angiotensin 2 receptor type I (ATR1) which is the native binding partner of ACE2 by 35% in terms of the calculated binding affinity. Strong binding is mediated through strong electrostatic attachments with every fourth residue on the N-terminus alpha-helix (starting from Ser19 to Asn53) as the turn of the helix makes these residues solvent accessible. By contrasting the spike protein SARS-CoV-2 Rosetta binding energy with ACE2 of different livestock and pet species we find strongest binding with bat ACE2 followed by human, feline, equine, canine and finally chicken. This is consistent with the hypothesis that bats are the viral origin and reservoir species. These results offer a computational explanation for the increased infectivity of SARS-CoV-2 and allude to therapeutic modalities by identifying and rank-ordering the ACE2 residues involved in binding with the virus.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • - Analysis of bat coronavirus RaTG13 added -Improved figures showing residue-residue interactions -Text improvements throughout the manuscript -Updated literature

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted May 11, 2020.
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Biophysical characterization of the SARS-CoV-2 spike protein binding with the ACE2 receptor and implications for infectivity
Ratul Chowdhury, Costas D. Maranas
bioRxiv 2020.03.30.015891; doi: https://doi.org/10.1101/2020.03.30.015891
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Biophysical characterization of the SARS-CoV-2 spike protein binding with the ACE2 receptor and implications for infectivity
Ratul Chowdhury, Costas D. Maranas
bioRxiv 2020.03.30.015891; doi: https://doi.org/10.1101/2020.03.30.015891

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