Expanding the Functional Scope of the Fmoc‐Diphenylalanine Hydrogelator by Introducing a Rigidifying and Chemically Active Urea Backbone Modification

Abstract

Peptidomimetic low‐molecular‐weight hydrogelators, a class of peptide‐like molecules with various backbone amide modifications, typically give rise to hydrogels of diverse properties and increased stability compared to peptide hydrogelators. Here, a new peptidomimetic low‐molecular‐weight hydrogelator is designed based on the well‐studied N ‐fluorenylmethoxycarbonyl diphenylalanine (Fmoc‐FF) peptide by replacing the amide bond with a frequently employed amide bond surrogate, the urea moiety, aiming to increase hydrogen bonding capabilities. This designed ureidopeptide, termed Fmoc—Phe—NHCONH—Phe—OH (Fmoc‐FuF), forms hydrogels with improved mechanical properties, as compared to those formed by the unmodified Fmoc‐FF. A combination of experimental and computational structural methods shows that hydrogen bonding and aromatic interactions facilitate Fmoc‐FuF gel formation. The Fmoc‐FuF hydrogel possesses properties favorable for biomedical applications, including shear thinning, self‐healing, and in vitro cellular biocompatibility. Additionally, the Fmoc‐FuF, but not Fmoc‐FF, hydrogel presents a range of functionalities useful for other applications, including antifouling, slow release of urea encapsulated in the gel at a high concentration, selective mechanical response to fluoride anions, and reduction of metal ions into catalytic nanoparticles. This study demonstrates how a simple backbone modification can enhance the mechanical properties and functional scope of a peptide hydrogel.

Supramolecular Hydrogel Induced by Electrostatic Interactions between Polycation and Phosphorylated-Fmoc-Tripeptide

“…In comparison, Fmoc-FF gels prepared by dissolution in DMSO followed by water dilution can reach a G' of 300 kPa at high peptide volume fraction. 26,50 Kinetically con-trolled self-assembly of Fmoc-FF using pH change induces a slower hydrogelation producing more homogeneous gels with low moduli, G' (G") being between 2 to 400 Pa (1.5 to 90 Pa). 28,51 The controlled self-assembly can be obtained either through steps of controlled temperature, 28 by Fmoc-FF colloid decomposition or mild change of pH.…”

Unusual Two‐Step Assembly of a Minimalistic Dipeptide‐Based Functional Hypergelator

“…Molecular dynamics is one simulation approach commonly utilized to investigate the self‐assembly behavior of peptides and peptide derivatives . To further explore the self‐assembly mechanism, we performed three microsecond coarse‐grained molecular dynamics (CG‐MD) simulations on systems consisting of 400 Fmoc‐Lys(Fmoc)‐Asp molecules in aqueous solutions containing ≈10% dimethyl sulfoxide (DMSO) in volume.…”

“…Simulations at low peptide concentrations, as experimentally used, are computationally intensive. In order to reduce the need of computational power and accelerate the assmebly process, we set the peptide concentrations in our simulations to be much higher, in accordence with previous simulation studies . Each Fmoc‐Lys(Fmoc)‐Asp molecule was modeled by 14 hydrophobic beads for the Fmoc groups, two negatively charged beads for the Asp group, and five beads for the Lys group (lysine is neutral).…”

Surface Triggered Self-Assembly of Fmoc-Tripeptide as an Antibacterial Coating

“…Fmoc-FF selfassemblies were employed as host hydrogels to incorporate silver nanoparticles to improve the antimicrobial response (Paladini et al, 2013). The backbone of this dipeptide was modified incorporating an urea moiety to inhibit the E. coli bacterial adhesion (Basavalingappa et al, 2019). Poorly soluble in water, Fmoc-FF peptide self-assembly is induced by dissolution in DMSO followed by a dilution step in water (Basavalingappa et al, 2019), by change of pH (Paladini et al, 2013), or by heating the solution, up to 90 • C for solubilization, followed by a cooling step (Kumar et al, 2016).…”

“…The backbone of this dipeptide was modified incorporating an urea moiety to inhibit the E. coli bacterial adhesion (Basavalingappa et al, 2019). Poorly soluble in water, Fmoc-FF peptide self-assembly is induced by dissolution in DMSO followed by a dilution step in water (Basavalingappa et al, 2019), by change of pH (Paladini et al, 2013), or by heating the solution, up to 90 • C for solubilization, followed by a cooling step (Kumar et al, 2016). To overcome these tedious processes, the enzyme assisted self-assembly (EASA) of peptides was introduced by Xu and co-workers (Yang et al, 2004;Yang and Xu, 2006).…”