A dense hydrogen‐bond network is responsible for the mechanical and structural properties of polysaccharides. Random derivatization alters the properties of the bulk material by disrupting the hydrogen bonds, but obstructs detailed structure–function correlations. We have prepared well‐defined unnatural oligosaccharides including methylated, deoxygenated, deoxyfluorinated, as well as carboxymethylated cellulose and chitin analogues with full control over the degree and pattern of substitution. Molecular dynamics simulations and crystallographic analysis show how distinct hydrogen‐bond modifications drastically affect the solubility, aggregation behavior, and crystallinity of carbohydrate materials. This systematic approach to establishing detailed structure–property correlations will guide the synthesis of novel, tailor‐made carbohydrate materials.

Biopolymers, like DNA and proteins, fold in specific conformations in order to exert complex biological functions. Synthetic modifications are commonly used to alter those conformations and create engineered biomaterials. In stark contrast, the chemical complexity and dynamic nature of polysaccharides have hampered a detailed structural characterization and structure−function correlations are still incomplete. Many synthetic strategies have been developed to access complex unnatural oligosaccharides, capable of mimicking or even improving the properties of the natural counterpart. However, the structural features behind these results are often neglected. This perspective highlights the approaches adopted to develop unnatural glycans, with a particular focus on how the insertion of specific modifications results in more flexible or more constrained structures. Synthetic analogues of natural oligosaccharides could shine light on fundamental structural features. The combination of modern synthetic, computational, and analytical methods will result in novel carbohydrate based foldamers, with defined shape and aggregation behavior. Multiple applications in biology, material science, and nanotechnology can be envisioned.

Cellulose is a polysaccharide that displays chirality across different scales, from the molecular to the supramolecular level. This feature has been exploited to generate chiral materials. To date, the mechanism of chirality transfer from the molecular level to higher-order assemblies has remained elusive, partially due to the heterogeneity of cellulose samples obtained via top-down approaches. Here, we present a bottom-up approach that uses well-defined cellulose oligomers as tools to understand the transfer of chirality from the single oligomer to supramolecular assemblies beyond the single cellulose crystal. Synthetic cellulose oligomers with defined sequences self-assembled into thin micrometer-sized platelets with controllable thicknesses. These platelets further assembled into bundles displaying intrinsic chiral features, directly correlated to the monosaccharide chirality. Altering the stereochemistry of the oligomer termini impacted the chirality of the self-assembled bundles and thus allowed for the manipulation of the cellulose assemblies at the molecular level. The molecular description of cellulose assemblies and their chirality will improve our ability to control and tune cellulose materials. The bottom-up approach could be expanded to other polysaccharides whose supramolecular chirality is less understood.

Ad ense hydrogen-bond network is responsible for the mechanical and structural properties of polysaccharides. Random derivatization alters the properties of the bulk material by disrupting the hydrogen bonds,b ut obstructs detailed structure-function correlations.W eh ave prepared well-defined unnatural oligosaccharides including methylated, deoxygenated, deoxyfluorinated, as well as carboxymethylated cellulose and chitin analogues with full control over the degree and pattern of substitution. Molecular dynamics simulations and crystallographic analysis showh ow distinct hydrogenbond modifications drastically affect the solubility,aggregation behavior,a nd crystallinity of carbohydrate materials.T his systematic approach to establishing detailed structure-property correlations will guide the synthesis of novel,t ailor-made carbohydrate materials.

Protein-glycan interactions mediate important biological processes,i ncluding pathogen host invasion and cellular communication. Herein, we showcase an expedite approach that integrates automated glycan assembly (AGA) of 19 F-labeled probes and high-throughput NMR methods,e nabling the study of protein-glycan interactions.Synthetic Lewis type 2a ntigens were screened against seven glycan binding proteins (GBPs), including DC-SIGN and BambL, respectively involved in HIV-1 and lung infections in immunocompromised patients,c onfirming the preference for fucosylated glycans (Le x ,H type 2, Le y ). Previously unknown glycanlectin weak interactions were detected, and thermodynamic data were obtained. Enzymatic reactions were monitored in real-time,d elivering kinetic parameters.T hese results demonstrate the utility of AGAc ombined with 19 FNMR for the discovery and characterization of glycan-protein interactions, opening up new perspectives for 19 F-labeled complex glycans.

In analogy to polypeptides and polynucleotides, polysaccharides tend to form helical secondary structures, as well as higher hierarchical assemblies. Nevertheless, the conformation of polysaccharides in solution remains in most cases elusive due to their intrinsic complexity and lack of analytical techniques. In this review, we discuss the different helical shapes adopted by polysaccharides, with particular focus on how the helical character is exploited to form supramolecular assemblies, such as inclusion complexes with linear guest molecules and co‐helices with polynucleotide strands. Several methodologies are used to tune the polysaccharides conformation, ranging from ion‐mediated coil‐helix transition to chemical synthesis of well‐defined compounds with specific modifications. The latter provides ideal tailor‐made probes for structural studies, with the aim to correlate their three‐dimensional structure and the macroscopic properties. Applications of oligosaccharides with defined shapes in molecular recognition and catalysis are envisioned.

Chitin, ap olymer composed of b(1-4)-linked Nacetyl-glucosamine monomers,a nd its partially deacetylated analogue chitosan,a re abundantb iopolymersw ith outstandingm echanical as well as elastic properties. Their degradation products,c hitooligosaccharides (COS), can trigger the innate immune response in humans and plants.B othm aterial and biological propertiesa re dependent on polymer length, acetylation,a sw ell as the pH. Withoutw ell-defined samples, ac omplete molecular descriptiono ft hese factors is still missing. Automated glycan assembly (AGA)e nabled rapid access to synthetic well-defined COS. Chitin-cellulose hybrid oligomers were prepared as importantt ools for as ystematic structural analysis. Intramolecular interactions, identified by molecular dynamics simulations and NMR analysis,u nderscore the importanceo ft he chitosana mino group for the stabilization of specific geometries.

Correlating the structures and properties of a polymer to its monomer sequence is key to understanding how its higher hierarchy structures are formed and how its macroscopic material properties emerge. Carbohydrate polymers, such as cellulose and chitin, are the most abundant materials found in nature whose structures and properties have been characterized only at the submicrometer level. Here, by imaging single-cellulose chains at the nanoscale, we determine the structure and local flexibility of cellulose as a function of its sequence (primary structure) and conformation (secondary structure). Changing the primary structure by chemical substitutions and geometrical variations in the secondary structure allow the chain flexibility to be engineered at the single-linkage level. Tuning local flexibility opens opportunities for the bottom-up design of carbohydrate materials.