Weak carbohydrate-carbohydrate interactions in membrane adhesion are fuzzy and generic

Carbohydrates such as the trisaccharide motif Le X are key constituents of cell surfaces. Despite intense research, the interactions between carbohydrates of apposing cells or membranes are not well understood. In this article, we investigate carbohydrate-carbohydrate interactions in membrane adhesion as well as in solution with extensive atomistic molecular dynamics simulations that exceed the simulation times of previous studies by orders of magnitude. For Le X , we obtain association constants of soluble carbohydrates, adhesion energies of lipid-anchored carbohydrates, and maximally sustained forces of carbohydrate complexes in membrane adhesion that are in good agreement with experimental results in the literature. Our simulations thus appear to provide a realistic, detailed picture of Le X -Le X interactions in solution and during membrane adhesion. In this picture, the Le X -Le X interactions are fuzzy, i.e. Le X pairs interact in a large variety of short-lived, bound conformations. For the synthetic tetrasaccharide Lac 2, which is composed of two lactose units, we observe similarly fuzzy interactions and obtain association constants of both soluble and lipid-anchored variants that are comparable to the corresponding association constants of Le X . The fuzzy, weak carbohydrate-carbohydrate interactions quantified in our simulations thus appear to be a generic feature of small, neutral carbohydrates such as Le X and Lac 2. Carbohydrates at membrane interfaces interact via a diversity of binding conformations which depends on the separation of the membranes.