When approaching a cell, viruses encounter a complex cell-surface environment where they must engage receptors to initiate infection. Many viruses have evolved to exploit the “forest” of sugars (cell-surface glycans) that covers the cell. These glycans often serve as an initial anchoring point. Because glycan chains are abundant at the cell surface, and because virions display multiple binding proteins, these interactions are highly multivalent. Through continuous making and breaking of individual bonds, multivalency shapes both how the virus binds to the cell and how it moves during the early stages of entry into the cell.
The cover image of the July 21 issue of Biophysical Journal artistically illustrates both the experimental approach and the mathematical model used to describe glycan–HPV16 interactions. Reflecting our microscopy-based experiments, fluorescently labeled HPV16 particles are shown landing on, and binding to, surface-tethered sugar chains, thereby establishing multiple virus-glycan contacts. The glycan surface acts as a well-controlled experimental model of the cell surface, while microscopic observations provide quantitative insights into arrival rate and particle residence time. Each virus particle can interact with several glycan chains in its vicinity and remains attached to the surface until all these bonds are broken. In our work, this process is captured by a continuous-time Markov chain model, simplified in the virion’s “speech bubble” in the cover image. This model links the kinetic properties of individual molecular bonds to the multivalent binding behavior observed for the whole virion and helps to reveal how multivalent interactions can modulate particle binding, unbinding, and rebinding. Particles bound at the surface can also diffuse laterally by repeatedly forming and breaking bonds with immobile glycan chains, as illustrated by the smaller particles near the surface in the background. In our study, we simulated this motion by using only two key molecular parameters: the single-molecule affinity between HPV16 and the glycan and the grafting density of the glycan chains on the surface.
The research shown in this article illustrates, at the single-virus level, the selective interaction between HPV16 and the glycan heparan sulfate, pointing to potential new therapeutic targets. In addition, it establishes a theoretical framework that links the binding kinetics and surface dynamics of multivalent virions to the properties of their underlying molecular interactions. This framework could be readily adapted to other highly multivalent biological systems. You can find more information on our work on the interaction between viruses and glycans and much more here.
— Dario Valter Conca, Fouzia Bano, Yara Abidine, Laura Soria Martinez, Kerstin Seier, Justas Svirelis, Andreas Dahlin, Mario Schelhaas, and Marta Bally