Infection of the human cell by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is mediated by a homotrimeric class I fusion protein, the spike (S), protruding from the viral membrane bilayer and covered in a sugar cloak made of 22 N-linked and at least 2 O-linked glycans per protomer. During this process, the spike’s receptor binding domain (RBD) transitions from a closed to an open state in order to recognize and bind to the angiotensin-converting enzyme 2 (ACE-2) receptor exposed on the host cell. In this work, exploiting the structural information rapidly become available at the beginning of the COVID-19 pandemic, we have developed a full-length model of the glycosylated SARS-CoV-2 S protein in the open and the closed states and used all-atom molecular dynamics to study the roles of glycans in this sophisticated molecular machinery along with its structural and dynamic properties. The simulations revealed the look of the glycan shield in the microsecond timescales, showing different vulnerabilities according to the spike’s state and topological domain. Beyond shielding, we identified two N-linked glycans located within the spike’s N-terminal domain at sites N165 and N234 stabilizing the RBD in the ‘up’ conformation. As further corroborated by biolayer interferometry experiments, these two glycans modulate the conformational plasticity of the RBD, priming the spike for infection. Overall, our work characterizes the structural and functional roles of glycans in the SARS-CoV-2 spike protein, dispensing critical insights that can be harnessed for vaccine design.

Glycans at sites N165 and N234 modulate the conformational plasticity of the SARS-CoV-2 spike’s receptor binding domain

ACS Fall 2021

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