Pelin JNBD et al. (2020), Self-Assembly, Nematic Phase Formation, and Org...

ECB-ART-48538

ACS Appl Mater Interfaces 2020 Mar 25;1212:13671-13679. doi: 10.1021/acsami.0c00686.

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Self-Assembly, Nematic Phase Formation, and Organocatalytic Behavior of a Proline-Functionalized Lipopeptide.

Pelin JNBD , Edwards-Gayle CJC , Castelletto V , Aguilar AM , Alves WA , Seitsonen J , Ruokolainen J , Hamley IW .

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The self-assembly of the amphiphilic lipopeptide PAEPKI-C16 (P = proline, A = alanine, E = glutamic acid, K = lysine, I = isoleucine, and C16 = hexadecyl) was investigated using a combination of microscopy, spectroscopy, and scattering methods and compared to that of C16-IKPEAP with the same (reversed) peptide sequence and the alkyl chain positioned at the N-terminus and lacking a free N-terminal proline residue. The catalytic activity of these peptides was then compared using a model aldol reaction system. For PAEPKI-C16, the cryo-TEM images showed the formation of micrometer-length fibers, which by small-angle X-ray scattering (SAXS) were found to have radii of 2.5-2.6 nm. Spectroscopic analysis shows that these fibers are built from β-sheets. This behavior is in complete contrast to that of C16-IKPEAP, which forms spherical micelles with peptides in a disordered conformation [Hutchinson J. Phys. Chem. B 2019, 123, 613]. In PAEPKI-C16, spontaneous alignment of fibers was observed upon increasing pH, which was accompanied by observed birefringence and anisotropy of SAXS patterns. This shows the ability to form a nematic phase, and unprecedented nematic hydrogel formation was also observed for these lipopeptides at sufficiently high concentrations. SAXS shows retention of an ultrafine (1.7 nm core radius) fibrillar network within the hydrogel. PAEPKI-C16 with free N-terminal proline shows enhanced anti:syn diastereoselectivity and better conversion compared to C16-IKPEAP. The cytotoxicity of PAEPKI-C16 was also lower than that of C16-IKPEAP for both fibroblast and cancer cell lines. These results highlight the sensitivity of lipopeptide properties to the presence of a free proline residue. The spontaneous nematic phase formation by PAEPKI-C16 points to the high anisotropy of its ultrafine fibrillar structure, and the formation of such a phase at low concentrations in aqueous solution may be valuable for future applications.

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Genes referenced: LOC100893907 LOC115919910 LOC579470 LOC588990 pelp1

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References [+] :

Aggeli, Self-assembling peptide polyelectrolyte beta-sheet complexes form nematic hydrogels. 2003, Pubmed

	Scheme 1. Molecular Structures of (Top) PAEPKI-C16 and (Bottom) C16-IKPEAP
	Figure 1. (a) Comparison of the concentration dependence of PAEPKI-C16 and the pyrene fluorescence I (393 nm). The inflection point of the curve intersection corresponds to the cac of each sample. (b) FTIR data of 2 wt % D2O solutions of the peptide, considering different concentrations and pH.
	Figure 2. CD spectra for 0.04 wt % PAEPKI-C16 water solutions at the pH conditions shown.
	Figure 3. Cryo-TEM images of 1 wt % PAEPKI-C16 at (a) native, (b) pH 8, and (c) pH 12.
	Figure 4. (a) SAXS data (gray symbols) and fitted form factors using a long cylindrical shell model (red lines) for 1 wt % PAEPKI-C16 water solutions, varying the pH. (b) Images of the birefringence of the samples in vials placed between crossed polarizers.
	Figure 5. Images of 5 wt % PAEPKI-C16 solutions at native, pH 8, and pH 12.
	Figure 6. (a) SEM image showing fiber structures in a pH 8 hydrogel. (b) SAXS data (gray) and fitted form factor (red) using a cylindrical shell model for 3 wt % PAEPKI-C16 hydrogels, at two pH values indicated. (c) Images of the birefringence between crossed polarizers of the 3 wt % samples. (d) Scheme of the electrospinning procedure and TEM images of the electrospun 5 wt % gel samples.
	Scheme 2. Aldol Reaction Mechanism Using p-Nitrobenzaldehyde and Cyclohexanone as Reagents, Catalyzed by PAEPKI-C16 at Native pH
	Figure 7. MTT assay of the viability of fibroblasts (HDFa) and breast cancer MCF-7 cells as a function of concentration of C16-IKPEAP and PAEPKI-C16.