Comparison of the Self-Assembly Behavior of Fmoc-Phenylalanine and Corresponding Peptoid Derivatives

Abstract

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.

Ultrashort Peptide Self-Assembly: Front-Runners to Transport Drug and Gene Cargos

“…The gel showed enhanced dye diffusion and faster gel erosion at higher temperature suggesting further exploration of the molecule in drug delivery (Singh et al, 2015). The unidirectional hydrogen bonding of the carbamate group within Fmoc-Phe-OH assemblies directed the assembly into 1D fibrils while Fmoc-peptoid analogs displayed 2D/3D morphology due to the alteration in H-bonding (Rajbhandary et al, 2018).…”

Understanding gel-to-crystal transitions in supramolecular gels

“…There is an argument that there is a link between the gel and crystal phase or at least there is sufficient structural similarity to infer packing in the gel from a crystal structure. [14][15][16][17][18][19][20][21][22] Important motifs that lead to specific types of one-dimensional interaction in certain crystal structures have been used to guide design of further analogues. It is not uncommon with this approach to grow crystals in one solvent mixture and infer information as to packing to design gelators for a completely different solvent system.…”

“…Others have also shown that crystals can be grown from the gel phase in a range of systems. 14,[36][37][38][39][40][41][42][43][44] This can be spontaneous. 45 For example, Andrews et al have shown a case where a metastable gel transforms to a crystal phase, leading them to suggest that for their case the gelation is the first stage of the crystallisation process.…”

Probing the Nature of Noncovalent Interactions in Dimers of Linear Tyrosine-Based Dipeptides

“…Once a high enough concentration of these vesicles accumulates, they are thought to fuse into tubes. 7,11,18 Finally, the nanotube comes together in a more piece-wise cooperative manner. It suggests that the side chains of adjacent FF dipeptides “zipper” together to form ringlike structures while stacking up into a tube.…”

“…11 Additionally, more extensive hydrogen bonding was found to allow for high-aspect-ratio packing, further stabilizing the nanotubes. 11 A similar study of phenylalanine–alanine nanotubes confirmed the presence of both (NH)H···O carbonyl hydrogen bonding. 16…”