Differential Dynamic Behavior of Prefusion Spike Proteins of SARS Coronaviruses 1 and 2

Abstract

Within the last two decades, severe acute respiratory syndrome (SARS) coronaviruses 1 and 2 (SARS-CoV-1 and SARS-CoV-2) have caused two major outbreaks. For reasons yet to be fully understood the COVID-19 outbreak caused by SARS-CoV-2 has been significantly more widespread than the 2003 SARS epidemic caused by SARS-CoV-1, despite striking similarities between the two viruses. One of the most variable genes differentiating SARS-CoV-1 and SARS-CoV-2 is the S gene that encodes the spike glycoprotein. This protein mediates a crucial step in the infection, i.e., host cell recognition and viral entry, which starts with binding to the host cell angiotensin converting enzyme 2 (ACE2) protein for both viruses. Recent structural and functional studies have shed light on the differential binding behavior of the SARS-CoV-1 and SARS-CoV-2 spike proteins. In particular, cryogenic electron microscopy (cryo-EM) studies show that ACE2 binding is preceded by a large-scale conformational change in the spike protein to expose the receptor binding domain (RBD) to its binding partner. Unfortunately, these studies do not provide detailed information on the dynamics of this activation process. Here, we have used an extensive set of unbiased and biased microsecond-timescale all-atom molecular dynamics (MD) simulations of SARS-CoV-1 and SARS-CoV-2 spike protein ectodomains in explicit solvent to determine the differential behavior of spike protein activation in the two viruses. Our results based on nearly 50 microseconds of equilibrium and nonequilibrium MD simulations indicate that the active form of the SARS-CoV-2 spike protein is considerably more stable than the active SARS-CoV-1 spike protein. Unlike the active SARS-CoV-2 spike, the active SARS-CoV-1 spike spontaneously undergoes a large-scale conformational transition to a pseudo-inactive state, which occurs in part due to interactions between the N-terminal domain (NTD) and RBD that are absent in the SARS-CoV-2 spike protein. Steered MD (SMD) simulations indicate that the energy barriers between active and inactive states are comparatively lower for the SARS-CoV-1 spike protein. Based on these results, we hypothesize that the greater propensity of the SARS-CoV-2 spike protein to remain in the active conformation contributes to the higher transmissibility of SARS-CoV-2 in comparison to SARS-CoV-1. These results strongly suggest that the differential binding behavior of the active SARS-CoV-1 and 2 spike proteins is not merely due to differences in their RBDs as other domains of the spike protein such as the NTD could play a crucial role in the effective binding process, which involves the prebinding activation. Therefore, our hypothesis predicts that mutations in regions such as the NTD, which is not directly involved in binding, may lead to a change in the effective binding behavior of the coronavirus.

A review of the potential of conventional and advanced membrane technology in the removal of pathogens from wastewater

“…Advanced membrane technology offers a promising solution in battling COVID-19 variants through hybrid and synergistic functionalities such as photocatalytic oxidation, distillation, and filtration. The COVID-19 variants mainly involve mutations in the gene encoding the spike protein of SARS-CoV-2, which is the major surface glycoprotein that forms the cell wall or capsid of the viruses [173] . For this reason, the ongoing membrane technology can be designed and developed by considering the features of the spike protein of the SARS-CoV-2 virus.…”

SARS-CoV-2 spike opening dynamics and energetics reveal the individual roles of glycans and their collective impact

“…19,20,[24][25][26] Opening pathways determined using steered MD and targeted MD have been reported. [26][27][28] More recently, extensive simulations using enhanced sampling techniques such as weighted ensemble 29 and fluctuation amplification of specific traits (FAST) adaptive sampling combined with Folding@home 30 have provided details of multiple pathways for the S-protein opening. Moreover, features of the energy landscape of these conformational transitions that are necessary for viral binding and entry are beginning to emerge.…”

“…The copyright holder for this preprint this version posted August 13, 2021. ; https://doi.org/10.1101/2021.08.12.456168 doi: bioRxiv preprint that are necessary for viral binding and entry are beginning to emerge. 27,28,31 A recent study by Amaro and coworkers has highlighted the functional role of glycans at N165 and N234 beyond shielding 24 based on separate equilibrium simulations of the Sprotein down and up states. When the RBD transitions to the up state, the glycan at N234 rotates into the resulting void, stablizing the up conformation.…”

Recent progress on the mutations of SARS-CoV-2 spike protein and suggestions for prevention and controlling of the pandemic

“…Therefore, SARS-CoV-2 is more infectious than SARS-CoV. Besides, mounting evidence showed that the recently discovered SARS-CoV-2 is more infectious than the isolate reported in Wuhan, China in late December 2019, partly due to the conformational changes caused by the spike mutation ( Gobeil et al, 2021 ; Kumar et al, 2020 ; Zhang et al, 2021 ).…”

“…The NTD (N-terminal domain) locates at 14–306 amino acids (aa) of the viral spike protein. NTD has obvious structural plasticity, involves prebinding activation and immune activation, and plays vital roles in the effective binding process and immune response together with the RBD domain ( Kumar et al, 2020 ; Liu et al, 2020 ; McCallum et al; Rosa et al, 2021 ). Moreover, the GTNGTKR motif at 72–78 aa of the NTD may be involved in recognizing other receptors/co-receptors besides the ACE2 ( Behloul et al, 2020 ).…”