Heptad stereotypy, S/Q layering, and remote origin of the SARS-CoV-2 fusion core

Abstract

The fusion of the SARS-CoV-2 virus with cells, a key event in the pathogenesis of Covid-19, depends on the assembly of a six-helix fusion core (FC) formed by portions of the spike protein heptad repeats (HR) 1 and 2. Despite the critical role in regulating infectivity, its distinctive features, origin, and evolution are scarcely understood. Thus, we undertook a structure-guided positional and compositional analysis of the SARS-CoV-2 FC, in comparison with FCs of related viruses, tracing its origin and ongoing evolution. We find that clustered amino acid substitutions within HR1, distinguishing SARS-CoV-2 from SARS-CoV-1, enhance local heptad stereotypy and increase sharply the FC serine-to-glutamine (S/Q) ratio, determining a neat alternate layering of S-rich and Q-rich subdomains along the post-fusion structure. Strikingly, SARS-CoV-2 ranks among viruses with the highest FC S/Q ratio, together with highly syncytiogenic respiratory pathogens (RSV, NDV), whereas MERS-Cov, HIV, and Ebola viruses display low ratios, and this feature reflects onto S/Q segregation and H-bonding patterns. Our evolutionary analyses reveal that the SARS-CoV-2 FC occurs in other SARS-CoV-1-like Sarbecoviruses identified since 2005 in Hong Kong and adjacent regions, tracing its origin to >50 years ago with a recombination-driven spread. Finally, current mutational trends show that the FC is varying especially in the FC1 evolutionary hotspot. These findings establish a novel analytical framework illuminating the sequence/structure evolution of the SARS-CoV-2 FC, tracing its long history within Sarbecoviruses, and may help rationalize the evolution of the fusion machinery in emerging pathogens and the design of novel therapeutic fusion inhibitors.

PolyQ length-based molecular encoding of vocalization frequency in FOXP2

“…Atomic level structural predictions using Raptor-X 92 ( Figures 4 C and S5 E) are in agreement with Paircoil2 in showing Q 1 and Q 2 , and flanking Q-rich regions, forming an antiparallel CC hairpin of two α-helices separated by a turn (hinge). The Cynopterus ortholog displayed the longest CC with Q-Q hydrogen bonds 93 and the proline region in Rhinolophus forms a random coil loop between Q 1 and Q 2 .…”

Identification of Potential Lead Compounds Targeting Novel Druggable Cavity of SARS-CoV-2 Spike Trimer by Molecular Dynamics Simulations

“…In the prefusion state, the RBD of S trimer in closed state (S closed ) rotates upward with counterclockwise rotation of the CH region resulting in open conformation (S open ) for binding to the cellular receptor ( Figure 1 ) [ 12 ]. Subsequently, the S trimer changes to the postfusion state with the loss of the NTD and the formation of the six-helical bundle (6-HB) facilitated by the interactions between HR1 and HR2 [ 13 , 14 ]. The conformational changes of S trimer induce the viral entry and infection, thus the inhibition of the process might be a new approach for drug design [ 15 ].…”