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An exploration of the SARS-CoV-2 spike receptor binding domain (RBD) – a complex palette of evolutionary and structural features

Dwipanjan Sanyal, View ORCID ProfileSourav Chowdhury, Vladimir N. Uversky, View ORCID ProfileKrishnananda Chattopadhyay
doi: https://doi.org/10.1101/2020.05.31.126615
Dwipanjan Sanyal
1Protein Folding and Dynamics Group, Structural Biology and Bioinformatics division, CSIR-Indian Institute of Chemical Biology, Kolkata-700 032, INDIA
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Sourav Chowdhury
2Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA
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  • For correspondence: sourav_chowdhury@fas.harvard.edu krish@iicb.res.in
Vladimir N. Uversky
3Department of Molecular Medicine and USF Health Byrd Alzheimer’s Research Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, USA
4Laboratory of New Methods in Biology, Institute for Biological Instrumentation of the Russian Academy of Sciences, Federal Research Center “Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences”, Pushchino, Moscow region 142290, Russia
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Krishnananda Chattopadhyay
1Protein Folding and Dynamics Group, Structural Biology and Bioinformatics division, CSIR-Indian Institute of Chemical Biology, Kolkata-700 032, INDIA
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  • For correspondence: sourav_chowdhury@fas.harvard.edu krish@iicb.res.in
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Abstract

SARS-CoV-2 spike protein (S) is associated with the entry of virus inside the host cell by recruiting its loop dominant receptor binding domain (RBD) and interacting with the host ACE2 receptor. Our study deploying a two-tier approach encompassing evolutionary and structural analysis provides a comprehensive picture of the RBD, which could be of potential use for better understanding the RBD and address its druggability issues. Resorting to an ensemble of sequence space exploratory tools including co-evolutionary analysis and deep mutational scans we provide a quantitative insight into the evolutionarily constrained subspace of the RBD sequence space. Guided by structure network analysis and Monte Carlo simulation we highlight regions inside the RBD, which are critical for providing structural integrity and conformational flexibility of the binding cleft. We further deployed fuzzy C-means clustering by plugging the evolutionary and structural features of discrete structure blocks of RBD to understand which structure blocks share maximum overlap based on their evolutionary and structural features. Deploying this multi-tier interlinked approach, which essentially distilled the evolutionary and structural features of RBD, we highlight discrete region, which could be a potential druggable pocket thereby destabilizing the structure and addressing evolutionary routes.

Competing Interest Statement

The authors have declared no competing interest.

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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 June 04, 2020.
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An exploration of the SARS-CoV-2 spike receptor binding domain (RBD) – a complex palette of evolutionary and structural features
Dwipanjan Sanyal, Sourav Chowdhury, Vladimir N. Uversky, Krishnananda Chattopadhyay
bioRxiv 2020.05.31.126615; doi: https://doi.org/10.1101/2020.05.31.126615
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An exploration of the SARS-CoV-2 spike receptor binding domain (RBD) – a complex palette of evolutionary and structural features
Dwipanjan Sanyal, Sourav Chowdhury, Vladimir N. Uversky, Krishnananda Chattopadhyay
bioRxiv 2020.05.31.126615; doi: https://doi.org/10.1101/2020.05.31.126615

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