The current COVID-19 crisis is fueled by SARS coronavirus 2 (SARS-CoV-2). While developing vaccines and treatments will help in the short term, understanding the variables that control transmission will aid in the long run.
The research indicates that a structure enabled by sugar molecules on the spike protein may be required for virus entrance and that breaking this structure may be a technique for virus transmission to be halted.
Covid-19 caused by Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is highly infectious, and transmission involves a number of processes that may be addressed by vaccines and treatments.
The ability of SARS-CoV-2 to connect to host cells and transfer its genetic material is critical to its lifecycle. It accomplishes this through its spike protein, which is composed of three distinct components: a transmembrane bundle that ties the spike to the virus, and two S subunits (S1 and S2) on the virus’s exterior.
The S1 component binds to a protein on the surface of human cells called ACE2, and the S2 subunit detaches and merges the viral and human cell membranes to infect a human cell. Although this process is well understood, the precise order in which it occurs has yet to be discovered. Understanding the microsecond-scale and atomic-level motions of these protein structures, however, could lead to the identification of possible COVID-19 therapy targets.
The researchers were particularly interested in the role of sugar compounds known as glycans on the spike protein. Using an all-atom structure-based model, they ran millions of simulations to examine if the quantity, type, and position of glycans play a role in the membrane fusion stage of viral cell entrance via mediating these intermediate spike forms. Such models allow you to forecast the journey of atoms over time while accounting for steric forces, or how neighboring atoms influence the movement of others.
The simulations demonstrated that glycans form a “cage” that captures the “head” of the S2 subunit, forcing it to stall in an intermediate state between when it detaches from the S1 subunit and when the viral and cell membranes merge. When the glycans were absent, the S2 subunit spent significantly less time in this shape.
The simulations also imply that maintaining the S2 head in a specific position promotes the S2 subunit in recruiting human host cells and fusing with their membranes by allowing the virus to extend small proteins known as fusion peptides. Indeed, glycosylation of S2 considerably increased the likelihood that a fusion peptide would extend to the host cell membrane, but in the absence of glycans, this was only a remote possibility.
This study, published in eLife, demonstrates how the glycosylation state can govern infectivity while also offering a much-needed structural framework for exploring the dynamics of this ubiquitous virus.
Image Credit: REUTERS / Octavio Jones
