Posttranslational modifications optimize the ability of SARS-CoV-2 spike for effective interaction with host cell receptors

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 119; no. 28; pp. 1 - 11
• Main Authors: Kapoor, Karan, Tajkhorshid, Emad
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 12.07.2022
• Subjects: Antibodies; Biological Sciences; Cell surface; Coronaviruses; COVID-19; COVID-19 - virology; Domains; Electron microscopy; Glycan; Glycoproteins; Glycosylation; Heterogeneity; Homology; Host Microbial Interactions; Humans; Lipids; Membranes; Molecular docking; Molecular dynamics; Palmitoylation; Physical Sciences; Polysaccharides; Protein Binding; Protein Processing, Post-Translational; Proteins; Receptor mechanisms; Receptors; Receptors, Cell Surface - metabolism; Respiratory diseases; SARS-CoV-2; Severe acute respiratory syndrome coronavirus 2; Spike glycoprotein; Spike Glycoprotein, Coronavirus - genetics; Spike Glycoprotein, Coronavirus - metabolism; Viral diseases; Viral infections; Virulence; Viruses; glycosylation; coronaviruses; molecular dynamics; structural dynamics; spike protein
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.2119761119

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein is the prime target for vaccines, diagnostics, and therapeutic antibodies against the virus. While anchored in the viral envelope, for effective virulence, the spike needs tomaintain structural flexibility to recognize the host cell surface receptors and bind to them, a property that can heavily depend upon the dynamics of the unresolved domains, most prominently the stalk. Construction of the complete, membrane-bound spike model and the description of its dynamics are critical steps in understanding the inner working of this key element of the viral infection by SARS-CoV-2. Combining homology modeling, protein–protein docking, and molecular dynamics (MD) simulations, we have developed a full spike structure in a native membrane. Multimicrosecond MD simulations of this model, the longest known single trajectory of the full spike, reveal conformational dynamics employed by the protein to explore the surface of the host cell. In agreement with cryogenic electron microscopy (cryo-EM), three flexible hinges in the stalk allow for global conformational heterogeneity of spike in the fully glycosylated system mediated by glycan–glycan and glycan–lipid interactions. The dynamical range of the spike is considerably reduced in its nonglycosylated form, confining the area explored by the spike on the host cell surface. Furthermore, palmitoylation of the membrane domain amplifies the local curvature that may prime the fusion. We show that the identified hinge regions are highly conserved in SARS coronaviruses, highlighting their functional importance in enhancing viral infection, and thereby, provide points for discovery of alternative therapeutics against the virus.