Capturing a Crucial ‘Disorder-to-Order Transition’ at the Heart of the Coronavirus Molecular Pathology—Triggered by Highly Persistent, Interchangeable Salt-Bridges
The COVID-19 origin debate has greatly been influenced by genome comparison studies of late, revealing the emergence of the Furin-like cleavage site at the S1/S2 junction of the SARS-CoV-2 Spike (FLCS<sub>Spike</sub>) containing its <i><sub>681</sub>PRRAR<sub>685&...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-02-01
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| Series: | Vaccines |
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| Online Access: | https://www.mdpi.com/2076-393X/10/2/301 |
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| author | Sourav Roy Prithwi Ghosh Abhirup Bandyopadhyay Sankar Basu |
| author_facet | Sourav Roy Prithwi Ghosh Abhirup Bandyopadhyay Sankar Basu |
| author_sort | Sourav Roy |
| collection | DOAJ |
| description | The COVID-19 origin debate has greatly been influenced by genome comparison studies of late, revealing the emergence of the Furin-like cleavage site at the S1/S2 junction of the SARS-CoV-2 Spike (FLCS<sub>Spike</sub>) containing its <i><sub>681</sub>PRRAR<sub>685</sub></i> 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 ‘<i>disorder-to-order</i> transition’ of the FLCS<sub>Spike</sub> (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 FLCS<sub>Spike</sub> 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 seem to be 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 preference for ionic bond formation, even with a lesser number of cationic residues at their potentially polybasic FLCS<sub>Spike</sub> patches. The interaction energies are suggestive of 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. The 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. |
| first_indexed | 2024-03-09T20:53:59Z |
| format | Article |
| id | doaj.art-e38e7a8650774637a3427b7942a63445 |
| institution | Directory Open Access Journal |
| issn | 2076-393X |
| language | English |
| last_indexed | 2024-03-09T20:53:59Z |
| publishDate | 2022-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Vaccines |
| spelling | doaj.art-e38e7a8650774637a3427b7942a634452023-11-23T22:26:50ZengMDPI AGVaccines2076-393X2022-02-0110230110.3390/vaccines10020301Capturing a Crucial ‘Disorder-to-Order Transition’ at the Heart of the Coronavirus Molecular Pathology—Triggered by Highly Persistent, Interchangeable Salt-BridgesSourav Roy0Prithwi Ghosh1Abhirup Bandyopadhyay2Sankar Basu3Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USADepartment of Botany, Narajole Raj College, Vidyasagar University, Midnapore 721211, IndiaTheoretical Neurosciences Group, Institute De Neurosciences Des Systems, Aix-Marseille University, 13005 Marseille, FranceDepartment of Microbiology, Asutosh College, University of Calcutta, 92, Shyama Prasad Mukherjee Rd., Bhowanipore, Kolkata 700026, IndiaThe COVID-19 origin debate has greatly been influenced by genome comparison studies of late, revealing the emergence of the Furin-like cleavage site at the S1/S2 junction of the SARS-CoV-2 Spike (FLCS<sub>Spike</sub>) containing its <i><sub>681</sub>PRRAR<sub>685</sub></i> 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 ‘<i>disorder-to-order</i> transition’ of the FLCS<sub>Spike</sub> (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 FLCS<sub>Spike</sub> 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 seem to be 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 preference for ionic bond formation, even with a lesser number of cationic residues at their potentially polybasic FLCS<sub>Spike</sub> patches. The interaction energies are suggestive of 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. The 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.https://www.mdpi.com/2076-393X/10/2/301COVID-19SARS-CoV-2Spike–Furin interactionFLCSdisorder-to-order transitionenthalpy entropy compensation |
| spellingShingle | Sourav Roy Prithwi Ghosh Abhirup Bandyopadhyay Sankar Basu Capturing a Crucial ‘Disorder-to-Order Transition’ at the Heart of the Coronavirus Molecular Pathology—Triggered by Highly Persistent, Interchangeable Salt-Bridges Vaccines COVID-19 SARS-CoV-2 Spike–Furin interaction FLCS disorder-to-order transition enthalpy entropy compensation |
| title | Capturing a Crucial ‘Disorder-to-Order Transition’ at the Heart of the Coronavirus Molecular Pathology—Triggered by Highly Persistent, Interchangeable Salt-Bridges |
| title_full | Capturing a Crucial ‘Disorder-to-Order Transition’ at the Heart of the Coronavirus Molecular Pathology—Triggered by Highly Persistent, Interchangeable Salt-Bridges |
| title_fullStr | Capturing a Crucial ‘Disorder-to-Order Transition’ at the Heart of the Coronavirus Molecular Pathology—Triggered by Highly Persistent, Interchangeable Salt-Bridges |
| title_full_unstemmed | Capturing a Crucial ‘Disorder-to-Order Transition’ at the Heart of the Coronavirus Molecular Pathology—Triggered by Highly Persistent, Interchangeable Salt-Bridges |
| title_short | Capturing a Crucial ‘Disorder-to-Order Transition’ at the Heart of the Coronavirus Molecular Pathology—Triggered by Highly Persistent, Interchangeable Salt-Bridges |
| title_sort | capturing a crucial disorder to order transition at the heart of the coronavirus molecular pathology triggered by highly persistent interchangeable salt bridges |
| topic | COVID-19 SARS-CoV-2 Spike–Furin interaction FLCS disorder-to-order transition enthalpy entropy compensation |
| url | https://www.mdpi.com/2076-393X/10/2/301 |
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