Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 298, Issue 4, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.jbc.2022.101814
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Funding
- National Science Foundation [CHE 1945465, OAC-1818253]
- National Institutes of Health [R01GM116961]
- Arkansas High Performance Computing Center - National Science Foundation
- Arkansas Economic Development Commission
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Within the last 2 decades, two major outbreaks have occurred due to severe acute respiratory syndrome coronaviruses 1 and 2 (SARS-CoV-1 and SARS-CoV-2). However, the 2019 pandemic caused by SARS-CoV-2 has been significantly more widespread than the 2003 SARS epidemic caused by SARS-CoV-1, despite similarities between the two viruses. This study found that the active form of the SARS-CoV-2 spike protein is more stable than that of SARS-CoV-1, and the energy barrier for activation is higher in SARS-CoV-2. These findings suggest that domains other than the receptor-binding domain, such as the N-terminal domain, may play a crucial role in the differential binding behavior of the spike proteins.
Within the last 2 decades, severe acute respiratory syndrome coronaviruses 1 and 2 (SARS-CoV-1 and SARS-CoV-2) have caused two major outbreaks; yet, for reasons not fully understood, the coronavirus disease 2019 pandemic caused by SARS-CoV-2 has been significantly more widespread than the 2003 SARS epidemic caused by SARS-CoV-1, despite striking similarities between these two viruses. The SARS-CoV-1 and SARSCoV-2 spike proteins, both of which bind to host cell angiotensin-converting enzyme 2, have been implied to be a potential source of their differential transmissibility. However, the mechanistic details of prefusion spike protein binding to angiotensin-converting enzyme 2 remain elusive at the molecular level. Here, we performed an extensive set of equilibrium and nonequilibrium microsecond-level all-atom molecular dynamics simulations of SARS-CoV-1 and SARS-CoV-2 prefusion spike proteins to determine their differential dynamic behavior. Our results indicate that the active form of the SARS-CoV-2 spike protein is more stable than that of SARS-CoV-1 and the energy barrier associated with the activation is higher in SARS-CoV-2. These results suggest that not only the receptor-binding domain but also other domains such as the N-terminal domain could play a crucial role in the differential binding behavior of SARS-CoV-1 and SARS-CoV-2 spike proteins.
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