Emily
Editor, Senior Moderator
https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC8875383/
Roy S, Ghosh P, Bandyopadhyay A, Basu S. Capturing a Crucial 'Disorder-to-Order Transition' at the Heart of the Coronavirus Molecular Pathology-Triggered by Highly Persistent, Interchangeable Salt-Bridges. Vaccines (Basel). 2022;10(2):301. Published 2022 Feb 16. doi:10.3390/vaccines10020301
Abstract
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 [SUB]681[/SUB]PRRAR[SUB]685[/SUB] 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 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.
Keywords: COVID-19, SARS-CoV-2, Spike–Furin interaction, FLCS, disorder-to-order transition, enthalpy entropy compensation, entropy arrest, salt-bridge dynamics, proteolytic cleavage
Roy S, Ghosh P, Bandyopadhyay A, Basu S. Capturing a Crucial 'Disorder-to-Order Transition' at the Heart of the Coronavirus Molecular Pathology-Triggered by Highly Persistent, Interchangeable Salt-Bridges. Vaccines (Basel). 2022;10(2):301. Published 2022 Feb 16. doi:10.3390/vaccines10020301
Abstract
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 [SUB]681[/SUB]PRRAR[SUB]685[/SUB] 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 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.
Keywords: COVID-19, SARS-CoV-2, Spike–Furin interaction, FLCS, disorder-to-order transition, enthalpy entropy compensation, entropy arrest, salt-bridge dynamics, proteolytic cleavage
