Fragment-Based Approach for Hierarchical Nanotube Assembly of Small Molecules in Aqueous Phase

A fragment-based approach has proven successful in drug design and protein assemblies, yet its potential for constructing biomaterials from simple organic building blocks remains underexplored, particularly for self-assembly in aqueous phases, where water disrupts intermolecular hydrogen bonding. To the best of our knowledge, this study introduces the first case of integrating fragments from self-assembling molecules to design a small organic molecule that forms novel hierarchical nanotubes with polymorphism. The molecule's compact design incorporates three structural motifs derived from known nanotube assemblies, enabling a hierarchical assembly process: individual molecules with two conformations form dimers, which organize into hexameric units. These hexamers further assemble into nanotubes comprising 2-, 5-, and 6-protofilament fibers. The nanofibers share a nearly identical asymmetric unit - a hexameric triangular plate - with similar axial and lateral interfaces. The lateral interface, involving interactions between phosphate groups and aromatic rings, exhibits plasticity, allowing slight rotational variations between adjacent units. This adaptability facilitates the formation of diverse nanofiber architectures, showcasing the flexibility of these systems in aqueous environments. By leveraging fragments of self-assembling molecules, this work demonstrates a straightforward strategy that combines conformational flexibility and self-assembling fragments to construct advanced supramolecular biomaterials from small organic building blocks in aqueous settings.