Glycine Substitution Effects on the Supramolecular Morphology and Rigidity of Cell‐Adhesive Amphiphilic Peptides

Abstract

Self‐assembling peptides that are capable of adopting β‐sheet structures can generate nanofibers that lead to hydrogel formation. Herein, to tune the supramolecular morphologies, mechanical properties, and stimuli responses of the hydrogels, we investigated glycine substitution in a β‐sheet‐forming amphiphilic peptide. Glycine substitution generally enhances conformational flexibility. Indeed, glycine substitution in an amphiphilic peptide weakened the hydrogels or even inhibited the gelation. However, unexpectedly, glycine substitution at the center of the peptide molecule significantly enhanced the hydrogel stiffness. The central glycine substitution affected the molecular packing and led to twisted β‐sheet structures and to nanofiber bundling, which likely led to the stiffened hydrogel. Importantly, the supramolecular structures were accurately predicted by molecular dynamics simulations, demonstrating the helpfulness of these techniques for the identification of self‐assembling peptides. The hydrogel formed by the amphiphilic peptide with the central glycine substitution had cell adhesive function, and showed a reversible thermal gel‐to‐sol transition. Thus, glycine substitution is effective in modulating self‐assembling structures, rheological properties, and dynamics of biofunctional self‐assembling peptides.

Hydrogel‐Stiffening and Non‐Cell Adhesive Properties of Amphiphilic Peptides with Central Alkylene Chains

“…We reported that A8G formed a hydrogel at 1.0 % (w/v) at 20°C in an acidic aqueous medium. [27] A8βAla and A8Abu bearing one and two carbon longer central alkylene chains than A8G also formed self-standing opaque hydrogels under identical conditions (Figure 1a, b). In rheological measurements using oscillatory viscometry, A8βAla in the aqueous medium showed storage modulus G' = 3.2 × 10 3 Pa and loss modulus G" = 2.9 × 10 2 Pa (Figure 2a).…”

“…[20,26] Recently, we reported that substitution of an alanine residue with glycine at the center of an amphiphilic peptide results in bundling of the nanofibers and enhanced mechanical properties of the hydrogel. [27] Unlike a terminal alkyl tail, internal alkylene chains with different lengths can influence not only the hydrophobicity but also the conformational flexibility and packing of the peptide molecules. Self-assembled peptide nanofibers bearing terminal alkyl tails are increasingly used as biomaterials to mimic an extracellular matrix, yet the influence of internal alkylene chains on self-assembly, nanofiber structure and biological properties remains poorly defined.…”

Recent Progress in the Design and Application of Supramolecular Peptide Hydrogels in Cancer Therapy

“…[100] MAX1I8 showed a faster gelation process than MAX1 (30 s vs 75 min to reach a G′ of 100 Pa), and formed hydrogel with a G′ as high as 1320 Pa after 2 h. However, Muraoka and coworkers showed that substitution of alanine with glycine (A8G, RADARADA(RADA) 2 ) in the middle of the RAD16 peptide ((RADA) 4 ) increased the stiffness of the hydrogel (G′ RADA16 = 265 Pa, G″ RADA16 = 42 Pa; G′ A8G = 469 Pa, G″ A8G = 56 Pa). [101] The enhanced stiffness of A8G probably resulted from the formation of twisted -sheet structures and nanofiber bundles due to a transition in the molecular packing. These results suggested that a balanced rigidity and flexibility of filament should be reached to achieve high stiffness.…”

Current Progress in Cross-Linked Peptide Self-Assemblies

“…As a result, cross-linked RADA-based peptide fibers form hydrogels with high mechanical strength. The mechanical strength of hydrogels can be further enhanced by replacing an alanine residue to glycine [ 56 ]. Self-assembled peptide fibers composed of β -hairpin structures with multiple hydrogen bonds by the introduction of a bend structure derived from repeated proline residues were reported by Schneider ( Figure 2 c) [ 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 ].…”

“…In pioneer works, amphiphilic peptides having hydrophobic alkyl chain at the termini of hydrophilic peptides have been designed, and their fundamental properties and applications to biomaterials have been investigated [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 ]. Currently, both amphiphilic peptides and other peptide-based self-assembly units have been found, enabling the design of peptide fibers with a variety of functions [ 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , …”