tetano
Editor, Senior Moderator
Int J Mol Sci
. 2020 Dec 23;22(1):E80.
doi: 10.3390/ijms22010080.
Multiple Recombination Events and Strong Purifying Selection at the Origin of SARS-CoV-2 Spike Glycoprotein Increased Correlated Dynamic Movements
Massimiliano S Tagliamonte[SUP] 1 2 [/SUP], Nabil Abid[SUP] 3 4 [/SUP], Stefano Borocci[SUP] 5 6 [/SUP], Elisa Sangiovanni[SUP] 5 [/SUP], David A Ostrov[SUP] 2 [/SUP], Sergei L Kosakovsky Pond[SUP] 7 [/SUP], Marco Salemi[SUP] 1 2 [/SUP], Giovanni Chillemi[SUP] 5 8 [/SUP], Carla Mavian[SUP] 1 2 [/SUP]
Affiliations
Abstract
Our evolutionary and structural analyses revealed that the severe acute respiratory syndrome (SARS) coronavirus 2 (SARS-CoV-2) spike gene is a complex mosaic resulting from several recombination events. Additionally, the fixation of variants has mainly been driven by purifying selection, suggesting the presence of conserved structural features. Our dynamic simulations identified two main long-range covariant dynamic movements of the novel glycoprotein, and showed that, as a result of the evolutionary duality, they are preserved. The first movement involves the receptor binding domain with the N-terminal domain and the C-terminal domain 2 and is maintained across human, bat and pangolin coronaviruses. The second is a complex network of long-range dynamics specific to SARS-CoV-2 involving the novel PRRA and the conserved KR*SF cleavage sites, as well as conserved segments in C-terminal domain 3. These movements, essential for host cell binding, are maintained by hinges conserved across human, bat, and pangolin coronaviruses glycoproteins. The hinges, located around Threonine 333 and Proline 527 within the N-terminal domain and C-terminal domain 2, represent candidate targets for the future development of novel pan-coronavirus inhibitors. In summary, we show that while recombination created a new configuration that increased the covariant dynamic movements of the SARS-CoV-2 glycoprotein, negative selection preserved its inter-domain structure throughout evolution in different hosts and inter-species transmissions.
Keywords: ACE2; COVID-19; S glycoprotein; SARS-CoV-2; bioinformatics; furin-like cleavage site; molecular dynamics; recombination.
. 2020 Dec 23;22(1):E80.
doi: 10.3390/ijms22010080.
Multiple Recombination Events and Strong Purifying Selection at the Origin of SARS-CoV-2 Spike Glycoprotein Increased Correlated Dynamic Movements
Massimiliano S Tagliamonte[SUP] 1 2 [/SUP], Nabil Abid[SUP] 3 4 [/SUP], Stefano Borocci[SUP] 5 6 [/SUP], Elisa Sangiovanni[SUP] 5 [/SUP], David A Ostrov[SUP] 2 [/SUP], Sergei L Kosakovsky Pond[SUP] 7 [/SUP], Marco Salemi[SUP] 1 2 [/SUP], Giovanni Chillemi[SUP] 5 8 [/SUP], Carla Mavian[SUP] 1 2 [/SUP]
Affiliations
- PMID: 33374797
- DOI: 10.3390/ijms22010080
Abstract
Our evolutionary and structural analyses revealed that the severe acute respiratory syndrome (SARS) coronavirus 2 (SARS-CoV-2) spike gene is a complex mosaic resulting from several recombination events. Additionally, the fixation of variants has mainly been driven by purifying selection, suggesting the presence of conserved structural features. Our dynamic simulations identified two main long-range covariant dynamic movements of the novel glycoprotein, and showed that, as a result of the evolutionary duality, they are preserved. The first movement involves the receptor binding domain with the N-terminal domain and the C-terminal domain 2 and is maintained across human, bat and pangolin coronaviruses. The second is a complex network of long-range dynamics specific to SARS-CoV-2 involving the novel PRRA and the conserved KR*SF cleavage sites, as well as conserved segments in C-terminal domain 3. These movements, essential for host cell binding, are maintained by hinges conserved across human, bat, and pangolin coronaviruses glycoproteins. The hinges, located around Threonine 333 and Proline 527 within the N-terminal domain and C-terminal domain 2, represent candidate targets for the future development of novel pan-coronavirus inhibitors. In summary, we show that while recombination created a new configuration that increased the covariant dynamic movements of the SARS-CoV-2 glycoprotein, negative selection preserved its inter-domain structure throughout evolution in different hosts and inter-species transmissions.
Keywords: ACE2; COVID-19; S glycoprotein; SARS-CoV-2; bioinformatics; furin-like cleavage site; molecular dynamics; recombination.