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Abstract Self‐assembled peptides are an emerging family of biomaterials that show great promise for a range of biomedical and biotechnological applications. Introducing and tuning the pH‐responsiveness of the assembly is highly desirable for improving their biological activities. Inspired by proteins with internal ionizable residues, we report a simple but effective approach to constructing pH‐responsive peptide assembly containing unnatural ionic amino acids with an aliphatic tertiary amine side chain. Through a combined experimental and computational investigation, we demonstrate that these residues can be accommodated and stabilized within the internal hydrophobic compartment of the peptide assembly. The hydrophobic microenvironment shifts their pKasignificantly from a basic pH typically found for free amines to a more biologically relevant pH in the weakly acidic range. The pH‐induced ionization and ionization‐dependent self‐assembly and disassembly are thoroughly investigated and correlated with the biological activity of the assembly. This new approach has unique advantages in tuning the pH‐responsiveness of self‐assembled peptides across a large pH range in a complex biological environment. We anticipate the ionizable amino acids developed here can be widely applicable to the synthesis and self‐assembly of many amphiphilic peptides with endowed pH‐responsive properties to enhance their biological activities toward applications ranging from targeted therapeutic delivery to proton transport.
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Capacity for increased surface area in the hydrophobic core of β ‐sheet peptide bilayer nanoribbons
Amphipathic peptides with amino acids arranged in alternating patterns of hydrophobic and hydrophilic residues efficiently self‐assemble intoβ‐sheet bilayer nanoribbons. Hydrophobic side chain functionality is effectively buried in the interior of the putative bilayer of these nanoribbons. This study investigates consequences on self‐assembly of increasing the surface area of aromatic side chain groups that reside in the hydrophobic core of nanoribbons derived from Ac‐(XKXE)2‐NH2peptides (X = hydrophobic residue). A series of Ac‐(XKXE)2‐NH2peptides incorporating aromatic amino acids of increasing molecular volume and steric profile (X = phenylalanine [Phe], homophenylalanine [Hph], tryptophan [Trp], 1‐naphthylalanine [1‐Nal], 2‐naphthylalanine [2‐Nal], or biphenylalanine [Bip]) were assessed to determine substitution effects on self‐assembly propensity and on morphology of the resulting nanoribbon structures. Additional studies were conducted to determine the effects of incorporating amino acids of differing steric profile in the hydrophobic core (Ac‐X1KFEFKFE‐NH2and Ac‐(X1,5KFE)‐NH2peptides, X = Trp or Bip). Spectroscopic analysis by circular dichroism (CD) and Fourier transform infrared (FT‐IR) spectroscopy indicatedβ‐sheet formation for all variants. Self‐assembly rate increased with peptide hydrophobicity; increased molecular volume of the hydrophobic side chain groups did not appear to induce kinetic penalties on self‐assembly rates. Transmission electron microscopy (TEM) imaging indicated variation in fibril morphology as a function of amino acid in the X positions. This study confirms that hydrophobicity of amphipathic Ac‐(XKXE)2‐NH2peptides correlates to self‐assembly propensity and that the hydrophobic core of the resulting nanoribbon bilayers has a significant capacity to accommodate sterically demanding functional groups. These findings provide insight that may be used to guide the exploitation of self‐assembled amphipathic peptides as functional biomaterials.
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- PAR ID:
- 10449016
- Publisher / Repository:
- Wiley Blackwell (John Wiley & Sons)
- Date Published:
- Journal Name:
- Journal of Peptide Science
- Volume:
- 27
- Issue:
- 9
- ISSN:
- 1075-2617
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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