Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an enveloped, positive-sense, single-stranded RNA virus that has emerged in Wuhan, China, at the end of 2019, causing the ongoing COVID-19 pandemic. Protruding from the SARS-CoV-2 spherical membrane bilayer is the spike (S), a homotrimeric fusion glycoprotein that recognizes and latches onto the angiotensin-converting enzyme 2 (ACE2) to promote host cell infection. Similar to other viral proteins, the SARS-CoV-2 S protein is cloaked by a sugary shield made of 22 N-glycans and two O-glycans per protomer. In the context of viral pathogenesis, SARS-CoV-2 S protein’s extensive glycosylation plays a critical role as it is used to thwart and evade the host immune response. Here, building on the available cryo-EM structures of the spike in the open and closed states, we used <i>in-silico </i>approaches to construct a full-length model of the glycosylated SARS-CoV-2 S protein, allowing for an atomic-level understanding and annotation of the roles of glycans. All-atom molecular dynamics simulations revealed that, despite covering a vast amount of the S protein surface area, the glycan shield changes depending on the conformational state (open or closed) of the protein. Moreover, beyond shielding, two N-linked glycans at positions N165 and N234 modulate the conformational dynamics of the spike’s receptor binding domain (RBD), which is responsible for ACE2 recognition. As corroborated by biolayer interferometry experiments, these two glycans are found to "load-and-lock" the RBD in the up conformation, priming the spike for infection. Overall, our results highlight the importance of glycans in the evasion of the host immune response and in the modulation of the RBD dynamics. Our work sheds light on the full structure of this critical target and points out opportunities, strategies and challenges for vaccine design and drug development.

All-atom molecular dynamics simulations reveal how glycans prime the SARS-CoV-2 spike protein for infection

ACS Spring Meeting 2021

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