Self-Assembly, Hydrogelation, and Nanotube Formation by Cation-Modified Phenylalanine Derivatives

Fluorenylmethoxycarbonyl-protected phenylalanine (Fmoc-Phe) derivatives are a privileged class of molecule that spontaneously self-assemble into hydrogel fibril networks. Fmoc-Phe-derived hydrogels are typically formed by dilution of the hydrogelator from an organic cosolvent into water, by dissolution of the hydrogelator under basic aqueous conditions followed by adjustment of the pH with acid, or by other external triggering forces, including sonication and heating. These conditions complicate biological applications of these hydrogels. Herein, we report C-terminal cation-modified Fmoc-Phe derivatives that are positively charged across a broad range of pH values and that can self-assemble and form hydrogel networks spontaneously without the need to adjust pH or to use an organic cosolvent. In addition, these cationic Fmoc-Phe derivatives are found to self-assemble into novel sheet-based nanotube structures at higher concentrations. These nanotube structures are unique to C-terminal cationic Fmoc-Phe derivatives; the parent Fmoc-Phe carboxylic acids form only fibril or worm-like micelle structures. Nanotube formation by the cationic Fmoc-Phe molecules is dependent on positive charge at the C-terminus, since at basic pH where the positive charge is reduced only fibrils/worm-like micelles are formed and nanotube formation is suppressed. These studies provide an important example of Fmoc-Phe derivatives that can elicit hydrogelation without organic cosolvent or pH modification and also provide insight into how subtle modification of structure can perturb the self-assembly pathways of Fmoc-Phe derivatives.