Proteins are at the center of cell life. The dominant view is that we must understand their structure and dynamics to understand how they function. In the cell, proteins are post-translationally modified. Key among these modifications is glycosylation, the attachment of sugar chains to the surface of proteins.

Glycosylation affects many secreted and membrane proteins. Glycans are dynamic and weakly interacting molecules, constantly shifting between different conformations. This dynamic behavior forms a 'glycan shield' around proteins, creating an entropic barrier that must be overcome by other proteins to bind or for inter-domain movements that would clash with the glycans.

The glycan shield's role becomes particularly evident when it acts as a chaperone, aiding protein folding. Interactions with the glycan shield can lead to an entropic penalty, influencing the selection of specific protein conformers and the rejection of others.

Glycans are involved in numerous cellular interactions. Their amphipathic nature allows them to form multiple hydrogen bonds with other glycans, proteins, and water and establish hydrophobic interactions with aromatic and non-polar groups on proteins. Thanks to their dynamic nature, glycan chains involved in post-translational modifications tend to form weak multivalent bonds that can constantly exchange.

Glycans can affect protein-protein interactions also by altering the local protein chemistry. For example, cytoplasmic glycans found on intrinsically disordered proteins appear to play a role in balancing and fine-tuning the process of liquid-liquid phase separation. Glycan-mediated interactions have also been suggested to alter the local phase of viruses in aerosols.

The nature of glycan-glycan interactions remains poorly understood. Understanding glycan shielding and glycan-mediated interactions is vital from a biomedical perspective. Changes in glycosylation can impact protein interactions, folding, the population of conformational ensembles, and ultimately function, potentially leading to unwanted protein aggregation, modification of multi-protein assemblies, and affecting the recognition of drugs. Altered glycosylation is a characteristic of cancers, offering hope for future drugs targeting specific glycoforms.

Historically, the pharmaceutical industry has largely overlooked glycans due to a lack of understanding. The SARS-CoV-2 pandemic has thrust glycosylation into the limelight. The critical role of glycan shielding in vaccine development has been a key factor in preventing the emergence of vaccine-resistant strains capable of immune escape. The scientific momentum generated during the pandemic has fostered interdisciplinary dialogue and prompted computational groups to address glycosylation in their research. This has highlighted the deficiencies in the theoretical understanding of glycosylation.

We stand on the precipice of a transformation of structural glycoproteomics. We must address challenges and establish a common language between experimentalists and computational groups.