Fmoc-3F-Phe-Arg-NH2 and Fmoc-3F-Phe-Asp-OH dipeptides undergo coassembly to form two-component nanofibril hydrogels. These hydrogels support the viability and growth of NIH 3T3 fibroblast cells. The supramolecular display of Arg and Asp at the nanofibril surface effectively mimics the integrin-binding RGD peptide of fibronectin, without covalent connection between the Arg and Asp functionality.

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.

Fluorenylmethoxycarbonyl-protected phenylalanine (Fmoc-Phe) derivatives are a privileged class of low molecular weight amino acid hydrogelators that undergo spontaneous selfassembly in water to form one-dimensional (1D) fibril networks. Structural studies indicate that these fibrils feature unidirectional hydrogen bonding and parallel π−π interactions (Fmoc−Fmoc and side chain benzyl−benzyl), which stabilize the 1D fibrils. However, the relative contribution of hydrogen bonding vs π−π interactions in these assemblies is not understood. Herein, we compare the selfassembly of Fmoc-Phe amino acids with corresponding Fmocprotected peptoid derivatives. The N-benzyl glycine-derived peptoid analogues exhibit altered hydrogen bonding ability and benzyl side chain presentation geometry relative to the parent Fmoc-Phe molecules. We found that Fmoc-peptoid analogues preferentially assemble into two-dimensional (2D) nano-and microsheets that ultimately adopt crystalline states, whereas the Fmoc-Phe amino acids assemble into 1D nanofibrils. Crystal diffraction analysis suggests that hydrogen bonding of the carbamate group within Fmoc-Phe assemblies may be crucial for directing unilateral 1D growth of fibrils, while alteration of these interactions in the peptoid analogues removes the possibility for hydrogen bonds involving the carbamate moiety and limits intermolecular interactions to π−π bonding, which favors assembly into 2D architectures.

Low molecular weight agents that undergo self-assembly into fibril networks with hydrogel properties are promising biomaterials. Most low molecular weight hydrogelators are discovered empirically or serendipitously due to imperfect understanding of the mechanisms of self-assembly, the packing structure of self-assembled materials, and how the self-assembly process corresponds to emergent hydrogelation. Herein, the mechanisms of self-assembly and hydrogelation of N-fluorenylmethoxycarbonyl diphenylalanine (Fmoc-PhePhe), a well-studied low molecular weight hydrogelator, is probed by systematic comparison with derivatives in which Phe residues are replaced by corresponding N-benzyl glycine peptoid (Nphe) analogs. Peptoids are peptidomimetics that shift display of side chain functionality from the a-carbon to the terminal nitrogen. This alters the hydrogen bonding capacity, the side chain presentation geometry, amide cis/trans isomerization equilibrium, and b-sheet potential of the peptoid relative to the corresponding amino acid in the context of peptidic polymers. It was found that amino acid/peptoid hybrids Fmoc-Phe-Nphe and Fmoc-Nphe-Phe have altered fibril self-assembly propensity and reduced hydrogelation capacity relative to the parent dipeptide, and that fibril self-assembly of the dipeptoid, Fmoc-Nphe-Nphe, is completely curtailed. These findings provide insight into the potential of low molecular weight peptoids and peptide/peptoid hybrids as hydrogelation agents and illuminate the importance of hydrogen bonding and p-p interaction geometry in facilitating self-assembly of Fmoc-Phe-Phe.