Metal-Ion-Induced Evolution of Phenylalanine Self-Assembly: Structural Polymorphism of Novel Metastable Intermediates

The self-assembly of aromatic amino acids has been widely studied due to their ability to form well-defined amyloid-like fibrillar structures. Herein, for the first time, we report the existence of different metastable intermediate states of diverse morphologies, for example, droplets, spheres, vesicles, flowers, and toroids, that are sequentially formed in aqueous medium during the self-assembly process of phenylalanine in the presence of different divalent (Zn²⁺, Cd²⁺, and Hg²⁺) and trivalent (Al³⁺, Ga³⁺, and In³⁺) metal ions having low pK_a values. Due to metal ion-amino acid coordination and strong hydrophobic interaction induced by these metal ions, spherical aggregates are obtained at the initial stage of the structural evolution and further transformed into other intermediate states. Our work may facilitate understanding of the role of metal ions in the amino acid self-assembly process and broaden future applications of the obtained nanostructures in drug delivery, tissue engineering, bioimaging, biocatalysis, and other fields.