Entropically-Driven Co-assembly of l-Histidine and l-Phenylalanine to Form Supramolecular Materials

Molecular self-and co-assembly allow the formation of diverse and well-defined supramolecular structures with notable physical properties. Among the associating molecules, amino acids are especially attractive due to their inherent biocompatibility and simplicity. The biologically active enantiomer of L-histidine (L-His) plays structural and functional roles in proteins but does not self-assemble to form discrete nanostructures. In order to expand the structural space to include L-His-containing materials, we explored the co-assembly of L-His with all aromatic amino acids, including phenylalanine (Phe), tyrosine (Tyr), and tryptophan (Trp), all in both enantiomeric forms. In contrast to pristine L-His, the combination of this building block with all aromatic amino acids resulted in distinct morphologies including fibers, rods, and flake-like structures. Electrospray ionization mass spectrometry (ESI-MS) indicated the formation of supramolecular co-assemblies in all six combinations, but time-of-flight secondary-ion mass spectrometry (ToF-SIMS) indicated the best seamless co-assembly occurs between L-His and L-Phe while in the other cases, different degrees of phase separation could be observed. Indeed, isothermal titration calorimetry (ITC) suggested the highest affinity between L-His and L-Phe where the formation of co-assembled structures was driven by entropy. In accordance, among all the combinations, the co-assembly of L-His and L-Phe produced single crystals. The structure revealed the formation of a 3D network with nanocavities stabilized by hydrogen bonding between-N (L-His) and-NH (L- Phe). Taken together, using the co-assembly approach we expanded the field of amino acid nanomaterials and showed the ability to obtain discrete supramolecular nanostructures containing L-His based on its specific interactions with L-Phe.