Analysis of the SARS-CoV-2 spike protein glycan shield reveals implications for immune recognition

TLDR

The study aims to analyze glycoforms of the SARS‑CoV‑2 spike protein, identify potential HLA‑presented peptides, and evaluate how glycosylation may modulate innate and adaptive immunity. The authors generated 3D models of spike glycoforms from HEK293‑derived structures and glycomics data, simulated them with molecular dynamics to assess glycan microheterogeneity effects on antigenicity, and identified HLA‑binding peptides. The models reveal that glycans extensively shield the spike surface—covering about 40%—except the ACE2 receptor‑binding domain, and this shielding is largely independent of glycoform composition.

Abstract

Here we have generated 3D structures of glycoforms of the spike (S) glycoprotein from SARS-CoV-2, based on reported 3D structures and glycomics data for the protein produced in HEK293 cells. We also analyze structures for glycoforms representing those present in the nascent glycoproteins (prior to enzymatic modifications in the Golgi), as well as those that are commonly observed on antigens present in other viruses. These models were subjected to molecular dynamics (MD) simulation to determine the extent to which glycan microheterogeneity impacts the antigenicity of the S glycoprotein. Lastly, we have identified peptides in the S glycoprotein that are likely to be presented in human leukocyte antigen (HLA) complexes, and discuss the role of S protein glycosylation in potentially modulating the innate and adaptive immune response to the SARS-CoV-2 virus or to a related vaccine. The 3D structures show that the protein surface is extensively shielded from antibody recognition by glycans, with the notable exception of the ACE2 receptor binding domain, and also that the degree of shielding is largely insensitive to the specific glycoform. Despite the relatively modest contribution of the glycans to the total molecular weight of the S trimer (17% for the HEK293 glycoform) they shield approximately 40% of the protein surface.