(233h) Modeling the Influence of Glycosylation on Protein Interaction

Glycosylation is an important posttranslational modification of proteins and plays a crucial role in protein interactions. It also needs to be understood for optimization of recombinant protein expression. We study 3D structures of several glycoproteins in atomistic detail starting from known crystal structures to examine the effect of oligosaccharides on glycoprotein structure to evaluate the accessibility of the oligosaccharide chains to glycan modifying enzymes. Computational methods for modeling glycoprotein structures are employed to understand how changes in site-specific oligosaccharide composition and structure influence 3D glycoprotein structure, protein oligomerization, and product quality attributes such as activity/efficacy, stability, and immunogenicity.

As an example we study the interaction of the receptor binding domain of the Spike protein of SARS-CoV-2 with the ACE2 receptor which under glycosylation leads to stronger and longer ranged binding interactions between the proteins. Particularly, at shorter distances the interactions are between residues of the proteins themselves whereas at larger distances these interactions are mediated by the glycans. We see a catch slip type behavior where interactions during pulling break and are taken over by new interactions forming. The dominant interaction mode are hydrogen bonds, but Lennard-Jones and electrostatic interactions are relevant as well.

T validate our methodology we also study a fully glycosylated computational model of the T Cell Receptor (TCR) bound to the peptide-Major Histocompatibility Complex. We find that weak glycan-protein or glycan-glycan interactions impact the equilibrated structure of the TCR and pMHC leading to an increase in the overall bond strength of the TCR-pMHC complex including the duration and energetic strength under constant load.

We generally determine that computational modeling can elucidate the importance of glycosylation in the context of protein interaction