Sterically-Confined Rearrangements of SARS-CoV-2 Spike Protein Control Cell Invasion

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is highly contagious, and transmission involves a series of processes that may be targeted by vaccines and therapeutics. During transmission, host cell invasion is controlled by a large-scale conformational change of the Spike protein. This conformational rearrangement leads to membrane fusion, which creates transmembrane pores through which the viral genome is passed to the host. During Spike-protein-mediated fusion, the fusion peptides must be released from the core of the protein and associate with the host membrane. Interestingly, the Spike protein possesses many post-translational modifications, in the form of branched glycans that flank the surface of the assembly. Despite the large number of glycosylation sites, until now, the specific role of glycans during cell invasion has been unclear. Here, we propose that glycosylation is needed to provide sufficient time for the fusion peptides to reach the host membrane, otherwise the viral particle would fail to enter the host. To understand this process, an all-atom model with simplified energetics was used to perform thousands of simulations in which the protein transitions between the prefusion and postfusion conformations. These simulations indicate that the steric composition of the glycans induces a pause during the Spike protein conformational change. We additionally show that this glycan-induced delay provides a critical opportunity for the fusion peptides to capture the host cell. This previously-unrecognized role of glycans reveals how the glycosylation state can regulate infectivity of this pervasive pathogen.

Role for N -glycans and calnexin-calreticulin chaperones in SARS-CoV-2 Spike maturation and viral infectivity

“…In the postfusion structure, five of these glycans (N1098, N1134, N1158, N1173, and N1194) are uniformly spaced at ~4-nm distance along the long axis of the S2 trimer ( 22 ). On the basis of molecular modeling, it is predicted that some of these carbohydrates may affect the rate of virus-host membrane fusion during entry ( 23 ).…”

Camel nanobodies broadly neutralize SARS-CoV-2 variants

“…5B). This region is key for the function of the spike, as discussed in the recent work on the spike elongation requiring a stable helical bundle at the core of the spike (22). The Asp985-Glu988 seems highly conserved as well, indicative of a preserve function and lack of immune surveillance due to the buried disposition of the region.…”

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“…SMOG 2 and OpenSMOG provide a versatile framework for defining structure-based models of arbitrarily complex molecular systems. The flexibility of this approach is highlighted by recent simulations of the SARS-CoV-2 spike protein 32 (Figure 3). For this system, there is much interest in understanding the influence that glycans may have on the functional dynamics.…”