Salt-Triggered Peptide Folding and Consequent Self-Assembly into Hydrogels with Tunable Modulus

Abstract

Intramolecular folding events, triggered by the presence of salt, induce the self-assembly of β-hairpin peptides into hydrogel networks at physiological conditions. At pH 7.4 and low ionic strength solution conditions, dilute, homogeneous solutions of peptide (≤2 wt %) exhibit the viscosity of pure water. Circular dichroism spectroscopy shows that, at pH 7.4 in the absence of salt, peptides are unfolded. By raising the ionic strength of the solution, electrostatic interactions between charged amino acids within the peptide are screened, and a β-hairpin conformation is adopted. Folded β-hairpin molecules supramolecularly assemble via hydrophobic collapse and hydrogen bonding into a three-dimensional hydrogel network. FTIR and X-ray scattering data demonstrate that these hydrogels are rich in β-sheet. Dynamic oscillatory rheological measurements demonstrate that the resultant supramolecular structure forms an elastic material whose structure, and thus modulus, can be tuned by salt concentration and temperature. Storage moduli of hydrogels increase with increasing salt concentration. Robust hydrogelation is also observed in cell growth media at physiological conditions. Transmission electron microscopy reveals that the hydrogel elasticity arises from a network nanostructure consisting of semiflexible fibrillar assemblies.

Low-Molecular-Weight Gels: The State of the Art

“…61 It is necessary to initially have the molecule in a more solvated state than at the end. This can be achieved by heating to improve solubility, initially dissolving in a good solvent before adding an anti-solvent, choosing a pH at which the molecule is soluble and then adjusting the pH in one of a number of different ways to render the molecule less soluble, 62 adding a salt to charge screen, 63 using a pro-gelator with a cleavable, solubilizing group, 64 or using a chemical or enzymatic reaction to generate the gelator in situ from suitable precursors. 65,66 To the best of our knowledge, there are no examples where a molecule is simply added to a solvent and gelation results (although there are many examples where ''instant'' gelation can be induced by mixing two components that react or interact to form a gelator on contact).…”

Peptide-based biopolymers in biomedicine and biotechnology

“…Pochan and Schneider have demonstrated that short amphiphilic peptides that fold into β-hairpin structures will self-assemble into injectable hydrogels that can be used for tissue engineering [236][237][238][239][240][241][242][243][244][245]. The 20-amino acid peptide is composed of two sequences of alternating valine and lysine residues, which have a high propensity for β-sheet formation, adjoining a strong β-turn forming tetrapeptide (-V D PPT-).…”

“…The 20-amino acid peptide is composed of two sequences of alternating valine and lysine residues, which have a high propensity for β-sheet formation, adjoining a strong β-turn forming tetrapeptide (-V D PPT-). The molecule is induced into an intramolecularly folded β-hairpin structure by various external stimuli including pH [236], temperature [237], salt [238], and light [240,244]. The alternating valine and lysine residues are oriented such that the molecule is amphiphilic and has one polar, lysine-rich face and one nonpolar, valine-rich face.…”

Redox modulated hydrogelation of a self-assembling short peptide amphiphile

“…Peptide self-assembly is driven by the orchestrated interaction of several intermolecular non-covalent forces including hydrogen bonding, π-π stacking, hydrophobic effect and electrostatic interactions. Environmental stimuli including pH [16][17][18][19], ionic strength and/or metal ions [18,[20][21][22], temperature [23], light [24] and enzyme-triggers [25], provide powerful approaches for modulating hydrogelation. Furthermore, introduction of microenvironment-sensitive amino acid residues into peptide sequences is also an important strategy for controlling peptide self-assembly and hydrogelation [9,[26][27][28].…”