Abstract
In spite of the abundance of glycoproteins in biological processes, relatively little three-dimensional structural data is available for glycan structures. Here, we study the structure and flexibility of the vast majority of mammalian oligosaccharides appearing in N- and O-glycosylated proteins using a bottom up approach. We report the conformational free-energy landscapes of all relevant glycosidic linkages as obtained from local elevation simulations and subsequent umbrella sampling. To the best of our knowledge, this represents the first complete conformational library for the construction of N- and O-glycan structures. Next, we systematically study the effect of neighboring residues, by extensively simulating all relevant trisaccharides and one tetrasaccharide. This allows for an unprecedented comparison of disaccharide linkages in large oligosaccharides. With a small number of exceptions, the conformational preferences in the larger structures are very similar as in the disaccharides. This, finally, allows us to suggest several efficient approaches to construct complete N- and O-glycans on glycoproteins, as exemplified on two relevant examples.
Highlights
Most of the processes in living cells take place via some form of carbohydrate interaction.[1]
How different types of glycans change the function of the glycoproteins often remains unsolved because of incomplete information on their
The conformations of glycans in conjugation with glycoproteins form a challenge both for experimental and theoretical methods. Their complexity is the result of the variety of possible monomeric units which are linked in a branched way and have differently populated conformational states
Summary
Most of the processes in living cells take place via some form of carbohydrate interaction.[1]. The carbohydrate moieties of glycoproteins, serve as biological markers at various stages of cellular differentiation and proliferation and play significant roles in cell−cell recognition, cell adhesion, and signal transduction. This broad range of functionality is attributed to their structural diversity in terms of size, sequence, branching, and linkage types that can be formed from a variety of possible monomeric units. Most of the experimentally solved biomolecular structures have undergone extensive manipulation of oligosaccharides before X-ray crystallography or NMR spectroscopy due to their inherent flexibility and high degree of coordination with water. The available X-ray structures either have different types of glycoforms than the physiologically relevant forms or show only short sequences of glycan units.
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