DNA Condensation Induced by a Star-Shaped Hexameric Cationic Surfactant.

The interactions between a star-shaped hexameric cationic quaternary ammonium surfactant PAHB and calf thymus DNA and induced DNA condensation were investigated by ζ-potential, dynamic light scattering, atomic force microscopy, isothermal titration calorimetry, ethidium bromide exclusion assay, circular dichroism, and cytotoxicity assay. With the addition of PAHB, long extended DNA molecules exhibit successive conformational transitions from elongated coil to a partially condensed cluster-like aggregate, to a globules-on-a-string structure, and then to a fully condensed globule until the saturation point of interaction between PAHB and DNA, which is slightly above their charge neutralization point. The efficient condensation is mainly produced by the strong attractive electrostatic interaction between the multiple positively charged headgroups of PAHB and negatively charged phosphate groups of DNA, and the hydrophobic interaction among the multiple alkyl chains of PAHB. Moreover the transition of the DNA conformation is also affected by the transitions of PAHB molecular conformation from star-shaped to claw-like and pyramid-like. Although the DNA conformation is significantly changed by PAHB, the DNA secondary structure does not display obvious variations, and the PAHB/DNA mixture does not show cytotoxicity when DNA is partially condensed. These results indicate that star-shaped oligomeric cationic surfactant is a potential condensing agent for gene transfection.

Disaggregation ability of different chelating molecules on copper ion-triggered amyloid fibers.

Dysfunctional interaction of amyloid-ß (Aß) with excess metal ions is proved to be related to the etiology of Alzheimer's disease (AD). Using metal-binding compounds to reverse metal-triggered Aß aggregation has become one of the potential therapies for AD. In this study, the ability of a carboxylic acid gemini surfactant (SDUC), a widely used metal chelator (EDTA), and an antifungal drug clioquinol (CQ) in reversing the Cu(2+)-triggered Aß(1-40) fibers have been systematically studied by using turbidity essay, BCA essay, atomic force microscopy, transmission electron microscopy, and isothermal titration microcalorimetry. The results show that the binding affinity of Cu(2+) with CQ, SDUC, and EDTA is in the order of CQ > EDTA > SDUC, while the disaggregation ability to Cu(2+)-triggered Aß(1-40) fibers is in the order of CQ > SDUC > EDTA. Therefore, the disaggregation ability of chelators to the Aß(1-40) fibers does not only depend on the binding affinity of the chelators with Cu(2+). Strong self-assembly ability of SDUC and π-π interaction of the conjugate group of CQ also contributes toward the disaggregation of the Cu(2+)-triggered Aß(1-40) fibers and result in the formation of mixed small aggregates.

Modulation of Aß(1-40) peptide fibrillar architectures by Aß-based peptide amphiphiles.

Modulation of the fibrillogenesis of amyloid peptide Aß(1-40) with two Aß-based peptide amphiphiles has been studied. Both peptide amphiphiles contain two alkyl chains but in different positions. The two alkyl chains of 2C12-Aß(11-17) are attached to the same terminus of Aß(11-17), while those of C12-Aß(11-17)-C12 are separately attached to opposite termini of Aß(11-17). Thioflavin T fluorescence spectroscopy shows that all the peptide amphiphiles promote the formation of the cross-ß-sheet structure of Aß(1-40) and the aggregation of Aß(1-40), while 2C12-Aß(11-17) does this more efficiently. The atom force microscopy images indicate that the modulations of these two peptide amphiphiles on the Aß(1-40) aggregation experience two distinct pathways. 2C12-Aß(11-17) leads to amorphous aggregates, whereas C12-Aß(11-17)-C12 generates short rodlike fibrils. However, Fourier transform infrared spectroscopy suggests that the amorphous aggregates and rodlike fibrils display similar secondary structures. This work suggests that the aggregation ability and the aggregate structures of the peptide amphiphiles significantly affect their interactions with Aß(1-40) and lead to different morphologies of the Aß(1-40) aggregates.

Self-assembly of Aß-based peptide amphiphiles with double hydrophobic chains.

Two peptide-amphiphiles (PAs), 2C(12)-Lys-Aß(12-17) and C(12)-Aß(11-17)-C(12), were constructed with two alkyl chains attached to a key fragment of amyloid ß-peptide (Aß(11-17)) at different positions. The two alkyl chains of 2C(12)-Lys-Aß(12-17) were attached to the same terminus of Aß(12-17), while the two alkyl chains of C(12)-Aß(11-17)-C(12) were separately attached to each terminus of Aß(11-17). The self-assembly behavior of both the PAs in aqueous solutions was studied at 25 °C and at pHs 3.0, 4.5, 8.5, and 11.0, focusing on the effects of the attached positions of hydrophobic chains to Aß(11-17) and the net charge quantity of the Aß(11-17) headgroup. Cryogenic transmission electron microscopy and atomic force microscopy show that 2C(12)-Lys-Aß(12-17) self-assembles into long stable fibrils over the entire pH range, while C(12)-Aß(11-17)-C(12) forms short twisted ribbons and lamellae by adjusting pHs. The above fibrils, ribbons, and lamellae are generated by the lateral association of nanofibrils. Circular dichroism spectroscopy suggests the formation of ß-sheet structure with twist and disorder to different extents in the aggregates of both the PAs. Some of the C(12)-Aß(11-17)-C(12) molecules adopt turn conformation with the weakly charged peptide sequence, and the Fourier transform infrared spectroscopy indicates that the turn content increases with the pH increase. This work provides additional basis for the manipulations of the PA's nanostructures and will lead to the development of tunable nanostructure materials.

Disassembly of amyloid fibrils by premicellar and micellar aggregates of a tetrameric cationic surfactant in aqueous solution.

We report a finding that not only the micelles but also the premicellar aggregates of a star-like tetrameric quaternary ammonium surfactant PATC can disassemble and clear mature ß-amyloid Aß(1-40) fibrils in aqueous solution. Different from other surfactants, PATC self-assembles into network-like aggregates below its critical micelle concentration (CMC). The strong self-assembly ability of PATC even below its CMC enables PATC to disaggregate the Aß(1-40) fibrils far below the charge neutralization point of the Aß(1-40) with PATC. There may be two key features of the fibril disassembly induced by the surfactant. First, the positively charged surfactant molecules bind with the negatively charged Aß(1-40) fibrils through electrostatic interaction. Second, the self-assembly of the surfactant molecules bound onto the Aß(1-40) fibrils disaggregate the fibrils, and the surfactant molecules form mixed aggregates with the Aß(1-40) molecules. The result reveals a structural approach of constructing efficient disassembly agents to mature ß-amyloid fibrils.

Facile disassembly of amyloid fibrils using gemini surfactant micelles.

The accumulation of a peptide of 38-43 amino acids, in the form of fibrillar plaques, was one of the essential reasons for Alzheimer's disease (AD). Discovering an agent that is able to disassemble and clear disease-associated Abeta peptide fibrils from the brains of AD patients would have critical implications not only in understanding the dynamic process of peptide aggregation but also in the development of therapeutic strategies for AD. This study reported a new finding that cationic gemini surfactant C(12)C(6)C(12)Br(2) micelles can effectively disassemble the Abeta(1-40) fibrils in vitro. Systematic comparisons with other surfactants using ThT fluorescence, AFM, and FTIR techniques suggested that the disassembly effectiveness of gemini surfactant micelles arises from their special molecular structure (i.e., positively bicharged head and twin hydrophobic chains). To track the disassembly process, systematic cryoTEM characterization was also done, which suggested a three-stage disassembly process: (i) Spherical micelles are first absorbed onto the Abeta fibrils because of attractive electrostatic interaction. (ii) Elongated fibrils then disintegrate into short pieces and form nanoscopic aggregates via synergistic hydrophobic and electrostatic interactions. (iii) Finally, complete disaggregation of fibrils and dynamic reassembly result in the formation of peptide/surfactant complexes.