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 SARS-CoV-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.
【저자키워드】 SARS-CoV-2, Coronavirus disease 2019, SARS-CoV, molecular dynamics, ACE2, angiotensin-converting enzyme 2, RBD, receptor-binding domain, PC, principal component, SARS-CoV, severe acute respiratory syndrome coronavirus, MD, molecular dynamics, SARS, Severe acute respiratory syndrome, conformational change, NTD, N-terminal domain, CoV, coronavirus, PDB, Protein Data Bank, SPR, surface plasmon resonance, RBM, receptor-binding motif, PCA, principal component analysis, DNA, dynamic network analysis, SMD, steered molecular dynamics, smFRET, single-molecule FRET,