Direct Imaging of Chirality Transfer Induced by Glycosidic Bond Stereochemistry in Carbohydrate Self-Assemblies

Carbohydrates, essential biological building blocks, exhibit functional mechanisms tied to their intricate stereochemistry. Subtle stereochemical differences, such as those between the anomers maltose and cellobiose, lead to distinct properties due to their differing glycosidic bonds; the former is digestible by humans, while the latter is not. This underscores the importance of precise structural determination of individual carbohydrate molecules for deeper functional insights. However, their structural complexity and conformational flexibility, combined with the high spatial resolution needed, have hindered direct imaging of carbohydrate stereochemistry. Here, we employ noncontact atomic force microscopy integrated with a data-efficient, multifidelity structure search approach accelerated by machine learning integration to determine the precise 3D atomic coordinates of two carbohydrate anomers on Au(111). We observe that the stereochemistry of the glycosidic bond regulates on-surface chiral selection in carbohydrate self-assemblies. The reconstructed models, validated against experimental data, provide reliable atomic-scale structural evidence, uncovering the origin of the on-surface chirality from carbohydrate anomerism. Our study confirms that nc-AFM is a reliable technique for real-space discrimination of carbohydrate stereochemistry at the single-molecule level, providing a pathway for bottom-up investigations into the structure–property relationships of carbohydrates in biological research and materials science.