Conformational phase spaces of N-glycans under the computational microscope

Glycans have an extremely important influence on all living matter on Earth. For instance, their occurrence in eukaryotic cells as post-translational modifications confers diverse functions to the underlying proteins. However, the so-called ‘sugar code’ that draws the connection between glycan structure and function still remains to be deciphered. Its unraveling is hampered by the vast amount of monosaccharide types, chemical substituents and linkages, resulting in a very large variety of glycan configurations. In addition, especially N-glycans are typically more flexible than proteins, a consequence of their many freely rotating torsion angles along the glycosidic bonds. The result is a large set of multiple conformations that can be adopted by each single (N-)glycan, opening a ‘third dimension’ of the sugar code beyond primary sequence and molecular topology.
The question remains to which extent this third dimension is biologically relevant, and if there exist relationships between the sequence, the three dimensional structure, and the function of (N-)glycans in their various biological environments. Computational techniques such as Molecular Dynamics (MD) simulations can be utilized to construct molecular glyco(protein) models and explore the many accessible glycan conformers in order to predict their function at the molecular level, a feature that very often cannot be covered by experimental techniques.