Entropically-Driven\nCo-assembly of l‑Histidine\nand l‑Phenylalanine to Form Supramolecular Materials

Molecular\nself- and co-assembly allow the formation of diverse\nand well-defined supramolecular structures with notable physical properties.\nAmong the associating molecules, amino acids are especially attractive\ndue to their inherent biocompatibility and simplicity. The biologically\nactive enantiomer of l-histidine (l-His) plays structural\nand functional roles in proteins but does not self-assemble to form\ndiscrete nanostructures. In order to expand the structural space to\ninclude l-His-containing materials, we explored the co-assembly\nof l-His with all aromatic amino acids, including phenylalanine\n(Phe), tyrosine (Tyr), and tryptophan (Trp), all in both enantiomeric\nforms. In contrast to pristine l-His, the combination of\nthis building block with all aromatic amino acids resulted in distinct\nmorphologies including fibers, rods, and flake-like structures. Electrospray\nionization mass spectrometry (ESI-MS) indicated the formation of supramolecular\nco-assemblies in all six combinations, but time-of-flight secondary-ion\nmass spectrometry (ToF-SIMS) indicated the best seamless co-assembly\noccurs between l-His and l-Phe while in the other\ncases, different degrees of phase separation could be observed. Indeed,\nisothermal titration calorimetry (ITC) suggested the highest affinity\nbetween l-His and l-Phe where the formation of co-assembled\nstructures was driven by entropy. In accordance, among all the combinations,\nthe co-assembly of l-His and l-Phe produced single\ncrystals. The structure revealed the formation of a 3D network with\nnanocavities stabilized by hydrogen bonding between -N (l-His) and -NH (l-Phe). Taken together, using the co-assembly\napproach we expanded the field of amino acid nanomaterials and showed\nthe ability to obtain discrete supramolecular nanostructures containing l-His based on its specific interactions with l-Phe.