Fluorine Substitution Tunes the Nanofiber Chirality of Supramolecular Hydrogels to Promote Cell Adhesion and Proliferation

Fluorine atoms confer desirable biophysical, chemical, and biological properties to peptides/proteins by participating in various intermolecular interactions with their environment, but they are rarely used to control supramolecular chirality and functional. Herein, to identify the effects of fluorine substitution on the chirality and function of supramolecular assemblies, C-2-symmetric benzene-paradicarboxamide-based phenylalanine (phe) derivatives and three monofluorinated variants that had a single fluorine atom on their benzyl side chain in either the ortho, meta, or para position were synthesized. The experimental and theoretical results clearly show that the resulting assembled fibrils were supported by multiple interactions, including hydrogen bonding, pi-pi stacking and C/O-H center dot center dot center dot F-C-Ar interactions. Compared to nonfluorinated analogs, fluorine and its ring position on the aromatic side chain dictated the type and strength of the F center dot center dot center dot H interaction and then induced changes in supramolecular chirality and fiber morphology. Further studies on cell behavior showed that the order of positive interaction between high-order supramolecular chirality (M, P) and molecular chirality (L, D) on cell proliferation and viability is LM> DM> LP> DP. These findings provide a protocol for leveraging fluorine atoms and their positional dependence on directing chiral nanostructures with desirable handedness and creating fluorinated supramolecular hydrogels as extracellular matrix-mimetic scaffolds for cell culture and regenerative medicine.