TY - JOUR
T1 - Posttranslational modifications optimize the ability of SARS-CoV-2 spike for effective interaction with host cell receptors
AU - Kapoor, Karan
AU - Chen, Tianle
AU - Tajkhorshid, Emad
N1 - ACKNOWLEDGMENTS. This study was supported by NIH Awards P41-GM104601 (to E.T.) and R01-GM123455 (to E.T.). Simulations were performed using computational resources provided by the Lawrence Livermore National Laboratory, the Oak Ridge Leadership Computing Facility, and Microsoft Azure under COVID-19 High Performance Computing (HPC) Consortium Grant MCB200183 (to K.K.) as well as by the Texas Advanced Computing Center under Leadership Resource Allocations (LRAC) Project MCB21003 (to E.T.).
This study was supported by NIH Awards P41-GM104601 (to E.T.) and R01-GM123455 (to E.T.). Simulations were performed using computational resources provided by the Lawrence Livermore National Laboratory, the Oak Ridge Leadership Computing Facility, and Microsoft Azure under COVID-19 High Performance Computing (HPC) Consortium Grant MCB200183 (to K.K.) as well as by the Texas Advanced Computing Center under Leadership Resource Allocations (LRAC) Project MCB21003 (to E.T.).
PY - 2022/7/12
Y1 - 2022/7/12
N2 - 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 to maintain 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.
AB - 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 to maintain 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.
KW - spike protein
KW - molecular dynamics
KW - glycosylation
KW - structural dynamics
KW - coronaviruses
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U2 - 10.1073/pnas.2119761119
DO - 10.1073/pnas.2119761119
M3 - Article
C2 - 35737823
SN - 0027-8424
VL - 119
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 28
M1 - e2119761119
ER -