Back to Search
Start Over
Dual nature of human ACE2 glycosylation in binding to SARS-CoV-2 spike
- Source :
- PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Proceedings of the National Academy of Sciences of the United States of America
- Publication Year :
- 2021
-
Abstract
- Significance The SARS-CoV-2 virus infects cells by docking the spike protein at its surface to a receptor protein exposed on human cells. Both receptor and spike are covered by sugars. With molecular dynamics simulations, we show that sugars attached to the N90 site of the human receptor interfere with binding to the virus, explaining reports of increased susceptibility to infection if N90 glycosylation is lost. By contrast, sugars at the human receptor N322 site strengthen the binding to spike by latching onto a site on spike that is targeted also by neutralizing antibodies. By characterizing the contrasting roles of sugars in the interaction between virus and host cells, we aid in the targeted development of neutralizing antibodies and SARS-CoV-2 fusion inhibitors.<br />Binding of the spike protein of SARS-CoV-2 to the human angiotensin-converting enzyme 2 (ACE2) receptor triggers translocation of the virus into cells. Both the ACE2 receptor and the spike protein are heavily glycosylated, including at sites near their binding interface. We built fully glycosylated models of the ACE2 receptor bound to the receptor binding domain (RBD) of the SARS-CoV-2 spike protein. Using atomistic molecular dynamics (MD) simulations, we found that the glycosylation of the human ACE2 receptor contributes substantially to the binding of the virus. Interestingly, the glycans at two glycosylation sites, N90 and N322, have opposite effects on spike protein binding. The glycan at the N90 site partly covers the binding interface of the spike RBD. Therefore, this glycan can interfere with the binding of the spike protein and protect against docking of the virus to the cell. By contrast, the glycan at the N322 site interacts tightly with the RBD of the ACE2-bound spike protein and strengthens the complex. Remarkably, the N322 glycan binds to a conserved region of the spike protein identified previously as a cryptic epitope for a neutralizing antibody. By mapping the glycan binding sites, our MD simulations aid in the targeted development of neutralizing antibodies and SARS-CoV-2 fusion inhibitors.
- Subjects :
- Glycan
Glycosylation
glycosylation
&
PROTEIN
Plasma protein binding
Molecular Dynamics Simulation
01 natural sciences
Epitope
03 medical and health sciences
chemistry.chemical_compound
FUNCTIONAL RECEPTOR
DOMAIN
0103 physical sciences
Humans
Binding site
Neutralizing antibody
Receptor
030304 developmental biology
nbsp
0303 health sciences
Multidisciplinary
010304 chemical physics
biology
READER
virus-host interaction
Chemistry
SARS-CoV-2
Biology and Life Sciences
Biological Sciences
Virus Internalization
molecular dynamics
Cell biology
carbohydrates (lipids)
Biophysics and Computational Biology
GLYCAN
Docking (molecular)
MOLECULAR-DYNAMICS
Spike Glycoprotein, Coronavirus
biology.protein
Angiotensin-Converting Enzyme 2
Antibody
ACE2 receptor
Protein Binding
SARS-CORONAVIRUS
Subjects
Details
- Language :
- English
- ISSN :
- 00278424 and 10916490
- Database :
- OpenAIRE
- Journal :
- PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Proceedings of the National Academy of Sciences of the United States of America
- Accession number :
- edsair.doi.dedup.....8d32e514e2d110612a2421144447441b