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

Om Shanker Tiwari, Ruth Aizen, Massimiliano Meli, Giorgio Colombo, Linda J.W. Shimon, Noam Tal, Ehud Gazit*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

8 Scopus citations


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.

Original languageEnglish
Pages (from-to)3506-3517
Number of pages12
JournalACS Nano
Issue number4
StatePublished - 28 Feb 2023


FundersFunder number
Airforce Research Laboratories
Air Force Office of Scientific ResearchFA8655-21-1-7004
Tel Aviv University


    • Co-assembly
    • aromatic amino acids
    • chirality
    • co-crystals
    • supramolecular materials


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