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Amphipathic peptides with amino acids arranged in alternating patterns of hydrophobic and hydrophilic residues efficiently self‐assemble into β‐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‐NH2 peptides (X = hydrophobic residue). A series of Ac‐(XKXE)2‐NH2 peptides 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‐NH2 and Ac‐(X1,5KFE)‐NH2 peptides, X = Trp or Bip). Spectroscopic analysis by circular dichroism (CD) and Fourier transform infrared (FT‐IR) spectroscopy indicated β‐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‐NH2 peptides 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. [ABSTRACT FROM AUTHOR]

Self‐assembled peptide materials have emerged as promising bioinspired tools for applications that include regenerative medicine, drug delivery, antimicrobial and vaccine development, optics, and catalysis. Peptide self‐assembly mediated by noncovalent hydrogen bonding, coulombic, hydrophobic, and aromatic interactions gives rise to a variety of supramolecular structures that reflect on the nature of the constituent peptides. The emergent properties of these supramolecular peptide materials often depend on the multivalent presentation of functional appendages on the self‐assembled scaffold. For example, the multivalent display of cell‐signaling motifs on self‐assembled peptide nanofibrils provides materials that are excellent extracellular matrix mimetics for tissue engineering applications. This review includes a discussion of chemical strategies that address the challenge of appending functional signal motifs in a multivalent display on self‐assembled peptide and protein materials. In addition, recent examples of supramolecular peptide materials that rely on the multivalent display of chemical signals for the desired applications are presented. Collectively, this discussion illustrates the potential of self‐assembled peptides as sustainable materials to address challenges in contemporary materials science and provides principles for the design of next‐generation agents for a variety of applications. [ABSTRACT FROM AUTHOR]

Low molecular weight agents that undergo self‐assembly into fibril networks with hydrogel properties are promising biomaterials. Most low molecular weight hydrogelators are discovered empirically or serendipitously due to imperfect understanding of the mechanisms of self‐assembly, the packing structure of self‐assembled materials, and how the self‐assembly process corresponds to emergent hydrogelation. Herein, the mechanisms of self‐assembly and hydrogelation of N‐fluorenylmethoxycarbonyl diphenylalanine (Fmoc‐PhePhe), a well‐studied low molecular weight hydrogelator, is probed by systematic comparison with derivatives in which Phe residues are replaced by corresponding N‐benzyl glycine peptoid (Nphe) analogs. Peptoids are peptidomimetics that shift display of side chain functionality from the α‐carbon to the terminal nitrogen. This alters the hydrogen bonding capacity, the side chain presentation geometry, amide cis/trans isomerization equilibrium, and β‐sheet potential of the peptoid relative to the corresponding amino acid in the context of peptidic polymers. It was found that amino acid/peptoid hybrids Fmoc‐Phe‐Nphe and Fmoc‐Nphe‐Phe have altered fibril self‐assembly propensity and reduced hydrogelation capacity relative to the parent dipeptide, and that fibril self‐assembly of the dipeptoid, Fmoc‐Nphe‐Nphe, is completely curtailed. These findings provide insight into the potential of low molecular weight peptoids and peptide/peptoid hybrids as hydrogelation agents and illuminate the importance of hydrogen bonding and π–π interaction geometry in facilitating self‐assembly of Fmoc‐Phe‐Phe. [ABSTRACT FROM AUTHOR]

Abstract: Crystalline microtubes formed by a spontaneous transition from self‐assembled hydrogel fibrils of Fmoc‐4‐NO2‐Phe act as optical waveguides when coassembled with amyloid‐binding fluorescent molecules. Specifically, thioflavin‐T (ThT), which exhibits amyloid‐specific fluorescence, coassembles with Fmoc‐4‐NO2‐Phe and is selectively confined to the interior of the resulting microtubes. These two‐component materials exhibit optical waveguide light transmission via internal reflectance in the interior cavity of the tube upon excitation of the ThT fluorophore. In addition, microtube assembly in the presence of both ThT and a fluorescence energy transfer (FRET) partner, propidium iodide (PI), results in three‐component crystalline microtubes that propagate incident energy via excitation of ThT and FRET excitation of PI. These optical waveguides are an example of amyloid‐inspired, multicomponent materials with the potential for use in light‐harvesting and energy‐transfer applications. [ABSTRACT FROM AUTHOR]

ABSTRACT Amphipathic peptides composed of alternating hydrophobic and hydrophilic amino acids are a privileged class of peptide, which have a high propensity to self-assemble into β-sheet fibrils. The Ac-(FKFE)2-NH2 peptide has been extensively studied and forms putative β-sheet bilayer fibrils in which the hydrophobic Phe side chains are organized to a single face of each constituent sheet; upon bilayer formation, these hydrophobic benzyl groups are sequestered in the hydrophobic core of the resulting fibril. In order for the Phe side chains to be uniformly displayed on one face of Ac-(FKFE)2-NH2 β-sheets, an antiparallel packing orientation in which one amino acid residue is unpaired must be adopted. Based on molecular models, we hypothesized that truncated seven amino acid derivatives of Ac-(FKFE)2-NH2 in which either the N-terminal Phe residue (Ac-KFEFKFE-NH2) or the C-terminal Glu residue (Ac-FKFEFKF-NH2) is eliminated should readily self-assemble into β-sheet bilayers in which all hydrogen bond and hydrophobic/charge interactions are satisfied. We found, however, that these minute changes in peptide sequence have unanticipated and dramatic effects on the self-assembly of each peptide. Ac-FKFEFKF-NH2 self-assembled into fibrils with unique morphology relative to the parent peptide, whereas the Ac-KFEFKFE-NH2 peptide had a strongly reduced propensity to self-assemble, even failing to self-assemble altogether under some conditions. These findings provide significant insight into the effect of sequence length and strand registry as well as hydrophobicity and charge on the self-assembly of simple amphipathic peptides to illuminate the possibility of tuning self-assembly processes and the resulting structures with minute changes to peptide sequence. © 2013 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 100: 738-750, 2013. [ABSTRACT FROM AUTHOR]

Amphipathic peptides composed of alternating polar and nonpolar residues have a strong tendency to self-assemble into one-dimensional, amyloid-like fibril structures. Fibrils derived from peptides of general (XZXZ) n sequence in which X is hydrophobic and Z is hydrophilic adopt a putative β-sheet bilayer. The bilayer configuration allows burial of the hydrophobic X side chain groups in the core of the fibril and leaves the polar Z side chains exposed to solvent. This architectural arrangement provides fibrils that maintain high solubility in water and has facilitated the recent exploitation of self-assembled amphipathic peptide fibrils as functional biomaterials. This article is a critical review of the development and application of self-assembling amphipathic peptides with a focus on the fundamental insight these types of peptides provide into peptide self-assembly phenomena. © 2011 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 98: 169-184, 2012. [ABSTRACT FROM AUTHOR]

Aromatic amino acids strongly promote cross-β amyloid formation; whether the amyloidogenicity of aromatic residues is due to high hydrophobicity and β-sheet propensity or formation of stabilizing π-π interactions has been debated. To clarify the role of aromatic residues on amyloid formation, the islet amyloid polypeptide 20-29 fragment [IAPP(20-29)], which contains a single aromatic residue (Phe 23), was adopted as a model. The side chain of residue 23 does not self-associate in cross-β fibrils of IAPP(20-29) (Nielsen et al., Angew Chem Int Ed 2009;48:2118-2121), allowing investigation of the amyloidogenicity of aromatic amino acids in a context where direct π-π interactions do not occur. We prepared variants of IAPP(20-29) in which Tyr, Leu, Phe, pentafluorophenylalanine (F5-Phe), Trp, cyclohexylalanine (Cha), α-naphthylalanine (1-Nap), or β-naphthylalanine (2-Nap) (in order of increasing peptide hydrophobicity) were incorporated at position 23 (SNNXGAILSS-NH2), and the kinetic and thermodynamic effects of these mutations on cross-β self-assembly were assessed. The Tyr, Leu, and Trp 23 variants failed to readily self-assemble at concentrations up to 1.5 m M, while the Cha 23 mutant fibrillized with attenuated kinetics and similar thermodynamic stability relative to the wild-type Phe 23 peptide. Conversely, the F5-Phe, 1-Nap, and 2-Nap 23 variants self-assembled at enhanced rates, forming fibrils with greater thermodynamic stability than the wild-type peptide. These results indicate that the high amyloidogenicity of aromatic amino acids is a function of hydrophobicity, β-sheet propensity, and planar geometry and not the ability to form stabilizing or directing π-π bonds. Proteins 2012;. © 2011 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Review: 166 refs. [ABSTRACT FROM AUTHOR]