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Capturing a crucial ‘disorder-to-order transition’ at the heart of the coronavirus molecular pathology – triggered by highly persistent, interchangeable salt-bridges

View ORCID ProfileSourav Roy, View ORCID ProfilePrithwi Ghosh, View ORCID ProfileAbhirup Bandyopadhyay, View ORCID ProfileSankar Basu
doi: https://doi.org/10.1101/2021.12.29.474439
Sourav Roy
1Dept of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, NC, 27834, USA
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Prithwi Ghosh
2Department of Botany, Narajole Raj College, Narajole, Paschim Medinipur, West Bengal, India
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Abhirup Bandyopadhyay
3Theoretical Neurosciences Group, Institute De Neurosciences Des Systems, Aix-Marseille University, France
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Sankar Basu
4Department of Microbiology, Asutosh College (affiliated to University of Calcutta), 92, Shyama Prasad Mukherjee Rd, Bhowanipore, Kolkata, West Bengal 700026, India
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  • For correspondence: nemo8130@gmail.com
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Abstract

The COVID-19 origin debate has greatly been influenced by Genome comparison studies of late, revealing the seemingly sudden emergence of the Furin-Like Cleavage Site at the S1/S2 junction of the SARS-CoV-2 Spike (FLCSSpike) containing its 681PRRAR685 motif, absent in other related respiratory viruses. Being the rate-limiting (i.e., the slowest) step, the host Furin cleavage is instrumental in the abrupt increase in transmissibility in COVID-19, compared to earlier onsets of respiratory viral diseases. In such a context, the current paper entraps a ’disorder-to-order transition’ of the FLCSSpike (concomitant to an entropy arrest) upon binding to Furin. The interaction clearly seems to be optimized for a more efficient proteolytic cleavage in SARS-CoV-2. The study further shows the formation of dynamically interchangeable and persistent networks of salt-bridges at the Spike–Furin interface in SARS-CoV-2 involving the three arginines (R682, R683, R685) of the FLCSSpike with several anionic residues (E230, E236, D259, D264, D306) coming from Furin, strategically distributed around its catalytic triad. Multiplicity and structural degeneracy of plausible salt-bridge network archetypes seems the other key characteristic features of the Spike–Furin binding in SARS-CoV-2 allowing the system to breathe – a trademark of protein disorder transitions. Interestingly, with respect to the homologous interaction in SARS-CoV (2002/2003) taken as a baseline, the Spike–Furin binding events generally in the coronavirus lineage seems to have a preference for ionic bond formation, even with lesser number of cationic residues at their potentially polybasic FLCSSpike patches. The interaction energies are suggestive of a characteristic metastabilities attributed to Spike–Furin interactions generally to the coronavirus lineage – which appears to be favorable for proteolytic cleavages targeted at flexible protein loops. T he current findings not only offer novel mechanistic insights into the coronavirus molecular pathology and evolution but also add substantially to the existing theories of proteolytic cleavages.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • Email addresses of all authors: Dr. Prithwi Ghosh: prithwi11{at}gmail.com, Dr. Sourav Roy: srvryt{at}gmail.com, Dr. Abhirup Bandyapadhyay: abhirupnit{at}gmail.com, Dr. Sankar Basu*: nemo8130{at}gmail.com

  • https://www.youtube.com/watch?v=wsHKpr9gZ9E

  • 7 FPR: False Positive Rate

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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 December 29, 2021.
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Capturing a crucial ‘disorder-to-order transition’ at the heart of the coronavirus molecular pathology – triggered by highly persistent, interchangeable salt-bridges
Sourav Roy, Prithwi Ghosh, Abhirup Bandyopadhyay, Sankar Basu
bioRxiv 2021.12.29.474439; doi: https://doi.org/10.1101/2021.12.29.474439
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Capturing a crucial ‘disorder-to-order transition’ at the heart of the coronavirus molecular pathology – triggered by highly persistent, interchangeable salt-bridges
Sourav Roy, Prithwi Ghosh, Abhirup Bandyopadhyay, Sankar Basu
bioRxiv 2021.12.29.474439; doi: https://doi.org/10.1101/2021.12.29.474439

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