The SARS-CoV-2 spike (S) is a type I fusion glycoprotein, responsible for initiating the infection leading to COVID-19. As a feature unique of SARS-CoV-2, the thick glycan shield covering the S protein is not only essential for hiding the virus from immune detection, but it also plays multiple functional roles, suggesting that the evolution of its sites of glycosylation is potentially intertwined with the evolution of the overall protein sequence to affect optimal activity. In this work we use multi-microsecond molecular dynamics simulations to characterize the structure and dynamics of different SARS-CoV-2 S models with different N-glycans at key functional sites, namely N234, N165 and N343. We also assessed the effect of a change in the SARS-CoV-2 S glycan shield’s topology due to recently acquired N-glycosites mutations. Our results indicate that the structures of the N-glycans at N234, N165 and N343 affect the stability of the active (or open) S conformation, and thus its exposure and accessibility. Furthermore, glycosylation at N370, just lost in CoV-2, is effective in stabilizing the open S conformation, yet it likely increases the RBD opening energetics, suggesting that the S glycan shield is indeed evolving, as well as the protein, to increase viral infectivity.

Fine-tuning the spike: Role of the nature and topology of the glycan shield in the structure and dynamics of SARS-CoV-2 S

ACS Fall 2021

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