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Distant Residues Modulate the Conformational Opening in SARS-CoV-2 Spike Protein

View ORCID ProfileDhiman Ray, View ORCID ProfileLy Le, Ioan Andricioaei
doi: https://doi.org/10.1101/2020.12.07.415596
Dhiman Ray
†Department of Chemistry, University of California Irvine, Irvine CA 92697
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Ly Le
†Department of Chemistry, University of California Irvine, Irvine CA 92697
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Ioan Andricioaei
‡‡Department of Physics and Astronomy, University of California Irvine, Irvine CA 92697
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Abstract

Infection of human cells by the novel coronavirus (SARS-Cov-2) involves the attachment of the receptor binding domain (RBD) of the spike protein to the peripheral membrane ACE2 receptors. The process is initiated by a down to up conformational change in the spike presenting the RBD to the receptor. Early stage computational and experimental studies on potential therapeutics have concentrated on the receptor binding domain, although this region is prone to mutations with the possibility of giving rise to widespread drug resistance. Here, using atomistic molecular dynamics simulation, we study the correlations between the RBD dynamics with physically distant residues in the spike protein, and provide a deeper understanding of their role in the infection, including the prediction of important mutations and of distant allosteric binding sites for therapeutics. Our model, based on time-independent component analysis (tICA) and protein graph connectivity network, was able to identify multiple residues, exhibiting long-distance coupling with the RBD opening dynamics. Mutation on these residues can lead to new strains of coronavirus with different degrees of infectivity and virulence. The most ubiquitous D614G mutation is predicted ab-initio from our model. Conversely, broad spectrum therapeutics like drugs and monoclonal antibodies can be generated targeting these key distant regions of the spike protein.

Significance statement The novel coronavirus SARS-CoV-2 has created the biggest pandemic of 21st century resulting in significant economic and public health crisis. Significant research effort for drug design against COVID-19 is focused on the receptor binding domain of the spike protein, although this region is prone to mutations causing resistance against therapeutics. We applied time-independent component analysis (tICA) and protein connectivity network model, on all-atom molecular dynamics trajectories, to identify key non-RBD residues, playing crucial role in the conformational transition facilitating spike-receptor binding and infection of human cell. These residues can not only be targeted by broad spectrum antibodies and drugs, mutations in them can generate new strains of coronavirus resulting in future epidemic.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • ↵* E-mail: andricio{at}uci.edu

  • https://doi.org/10.5281/zenodo.4310268

  • https://github.com/dhimanray/COVID-19-correlation-work.git

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 08, 2020.
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Distant Residues Modulate the Conformational Opening in SARS-CoV-2 Spike Protein
Dhiman Ray, Ly Le, Ioan Andricioaei
bioRxiv 2020.12.07.415596; doi: https://doi.org/10.1101/2020.12.07.415596
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Distant Residues Modulate the Conformational Opening in SARS-CoV-2 Spike Protein
Dhiman Ray, Ly Le, Ioan Andricioaei
bioRxiv 2020.12.07.415596; doi: https://doi.org/10.1101/2020.12.07.415596

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