Metastable hydrogels from aromatic dipeptides.

We demonstrate that the well-known self-assembling dipeptide diphenylalanine (FF) and its amidated derivative (FF-NH2) can form metastable hydrogels upon sonication of the dipeptide solutions. The hydrogels show instantaneous syneresis upon mechanical contact resulting in rapid expulsion of water and collapse into a semi-solid gel.

Co-assembly of tetrapeptides into complex pH-responsive molecular hydrogel networks.

Here we prepare pH-responsive complex molecular hydrogels from oppositely charged tetrapeptidic components that can be pH-tuned resulting in interconversion between different networks. Two different systems are described based on tetrapeptides with an alternating sequence of non-polar (F) and polar (D or K) residues. Co-aggregated hydrogels are easily formed in situ at neutral pH whereas one-component networks are maintained after changing into acidic or basic pH. These systems have been applied for the pH selective release of two hydrophobic dyes - Methylene Blue and Bromothymol Blue - as drug models. Different release profiles have been observed depending on the characteristics of the network as well as the pH of the media. These materials offer great potential as multidrug carriers.

Tuning chelation by the surfactant-like peptide A6H using predetermined pH values.

We examine the self-assembly of a peptide A6H comprising a hexa-alanine sequence A6 with a histidine (H) "head group", which chelates Zn(2+) cations. We study the self-assembly of A6H and binding of Zn(2+) ions in ZnCl2 solutions, under acidic and neutral conditions. A6H self-assembles into nanotapes held together by a ß-sheet structure in acidic aqueous solutions. By dissolving A6H in acidic ZnCl2 solutions, the carbonyl oxygen atoms in A6H chelate the Zn(2+) ions and allow for ß-sheet formation at lower concentrations, consequently reducing the onset concentration for nanotape formation. A6H mixed with water or ZnCl2 solutions under neutral conditions produces short sheets or pseudocrystalline tapes, respectively. The imidazole ring of A6H chelates Zn(2+) ions in neutral solutions. The internal structure of nanosheets and pseudocrystalline sheets in neutral solutions is similar to the internal structure of A6H nanotapes in acidic solutions. Our results show that it is possible to induce dramatic changes in the self-assembly and chelation sites of A6H by changing the pH of the solution. However, it is likely that the amphiphilic nature of A6H determines the internal structure of the self-assembled aggregates independent from changes in chelation.

Influence of the solvent on the self-assembly of a modified amyloid beta peptide fragment. II. NMR and computer simulation investigation.

The conformation of a model peptide AAKLVFF based on a fragment of the amyloid beta peptide Abeta16-20, KLVFF, is investigated in methanol and water via solution NMR experiments and molecular dynamics computer simulations. In previous work, we have shown that AAKLVFF forms peptide nanotubes in methanol and twisted fibrils in water. Chemical shift measurements were used to investigate the solubility of the peptide as a function of concentration in methanol and water. This enabled the determination of critical aggregation concentrations. The solubility was lower in water. In dilute solution, diffusion coefficients revealed the presence of intermediate aggregates in concentrated solution, coexisting with NMR-silent larger aggregates, presumed to be beta-sheets. In water, diffusion coefficients did not change appreciably with concentration, indicating the presence mainly of monomers, coexisting with larger aggregates in more concentrated solution. Concentration-dependent chemical shift measurements indicated a folded conformation for the monomers/intermediate aggregates in dilute methanol, with unfolding at higher concentration. In water, an antiparallel arrangement of strands was indicated by certain ROESY peak correlations. The temperature-dependent solubility of AAKLVFF in methanol was well described by a van't Hoff analysis, providing a solubilization enthalpy and entropy. This pointed to the importance of solvophobic interactions in the self-assembly process. Molecular dynamics simulations constrained by NOE values from NMR suggested disordered reverse turn structures for the monomer, with an antiparallel twisted conformation for dimers. To model the beta-sheet structures formed at higher concentration, possible model arrangements of strands into beta-sheets with parallel and antiparallel configurations and different stacking sequences were used as the basis for MD simulations; two particular arrangements of antiparallel beta-sheets were found to be stable, one being linear and twisted and the other twisted in two directions. These structures were used to simulate circular dichroism spectra. The roles of aromatic stacking interactions and charge transfer effects were also examined. Simulated spectra were found to be similar to those observed experimentally (in water or methanol) which show a maximum at 215 or 218 nm due to pi-pi* interactions, when allowance is made for a 15-18 nm red-shift that may be due to light scattering effects.

Synthesis, aggregation, and binding behavior of synthetic amphiphilic receptors.

Amphiphilic bowl-shaped receptor molecules have been synthesized starting from diphenylglycoluril. Upon dispersion in water, these molecules self-assemble to form vesicles that bind neutral guests and alkali metal ions. In the case of bis(alkylester)-modified receptor compound 4, electron microscopy reveals that an increase in the size of the alkali metal ion (from Na(+) or K(+) to Rb(+) and to Cs(+)) leads to a change in the shape of the aggregates, viz. from vesicles to tubules. Monolayer experiments suggest that this behavior is due to a change in the conformation of this amphiphilic receptor. In water, molecules of 4 have an elongated conformation that changes to a sandwich-like one upon binding of alkali metal ions. Binding studies with vesicles from the bis-ammonium receptors 6 and 9 and the guest 4-(4-nitrophenylazo)resorcinol (Magneson) reveal that below the critical aggregation concentration (CAC) of the amphiphile 1:1 host-guest complexes are formed with high host-guest association constants. Above the CAC, a host-guest ratio of 2:1 was observed that indicates that only the cavities on the outside of the vesicle can be occupied. In the case of the naphthalene walled compound 8 changes in the vesicle structure are induced by the organic guest Magneson.