Peptide-based foldamers for applications in self-recognition, supramolecular propagation, and photo-induced folding.

Abstract Self-recognition and propagation Two appropriately functionalized nucleobases, thymine and adenine, have been covalently linked at the N- and C-termini of α-aminoisobutyric acid-rich helical peptide foldamers, at a set of selected chromophores and at fully adenine-capped gold nanoparticles, aiming at driving self-assembly through complementary recognition. These systems were studied in terms of their self-recognition abilities to generate ordered nano-architectures. A crystal-state analysis (by X-ray diffraction) shows that adenine···thymine base pairing, through Watson–Crick intermolecular H-bonding, does take place between either end of each peptide molecule. Evidence for time-dependent foldamer···foldamer associations in solution is provided by circular dichroism measurements. The self-assembly of foldamers, through living supramolecular polymerization, eventually leads to the formation of twisted fibers. It was found that adenine···thymine binding allowed the formation of precisely assembled nano-systems that depend powerfully on their morphologies from the nature of the chromophores utilized. These well-organized supramolecular architectures are able to undergo morphologically self-shaping processes under illumination by visible light, through the activation of the plasmon resonance of gold nanoparticles. Moreover, three building blocks have been designed to chemically link to a gold surface and vertically self-assemble through thymine–adenine hydrogen bonds. Starting from these building blocks, two different films were engineered on gold surface. These films were characterized by electrochemical and spectroscopic techniques, and were very stable over time and when in contact with solution. Under illumination, they generate current with higher efficiency than similar previously described systems. Self-recognition and polymerization A set of four organogelators, from an α-amino acid derivative to a tetrapeptide, covalently linked to an acetylenic moiety, was studied in terms of polymerization efficiencies to afford peptide polyacetylenes (PAs) and polydiacetylenes (PdAs). Peptides were designed to improve the organogelator behavior via formation of intermolecular H-bonding-mediated β-sheet networks as a function of their main chain length. The polymerization experiments were run under appropriate conditions for the various monomers with the aim at elucidating how the monomer self-assembly process might influence polymer formation. Starting compounds and their corresponding polymers were characterized by a variety of spectroscopic and microscopic techniques. A symmetrical dipeptide-based diacetylene system (DAs) was found to be able to self-assemble in dichloromethane and to form a compact fiber network which resulted in a stable organogel. As a consequence of the organogel formation, we explored the possibility to run a light-induced topochemical polymerization. Evidence for the generation of peptide-based polydiacetylenes is provided by Raman, UV-Vis, and CD spectroscopies and a set of microscopic techniques. Finally, we succeeded in processing a polymeric composite by use of the electrospinning technique, starting from a mixture of a dipeptide-based diacetylene and polymethyl methacrylate. Photo-induced supramolecular folding Peptides are well known to play a fundamental therapeutic role and to represent building blocks for numerous useful biomaterials. Stabilizing their active 3D-structure by appropriate modifications remains, however, a challenge. We have expanded the available literature information on the conformational propensities of a promising backbone change of a terminally blocked δ-amino acid residue, a dipeptide mimic, by replacing its central amide moiety with an (E) Cγ=Cβ alkene unit. By DFT calculations, X-ray diffraction in the crystalline state, and FT-IR and NMR spectroscopies in solution we examined the extended vs. folded preferences of analogs of this prototype system. The theoretical and experimental results obtained clearly point to the conclusion that increasing the number of adequately positioned methylations will enhance the preference of the original sequence to fold, thus opening interesting perspectives in the design of conformationally constrained peptidomimetics. Systems in which an external stimulus elicits a response through some sort of modification at the molecular or supramolecular level bear potential for the development of smart materials and devices. A simple, unsaturated, E–Z photoisomerizable β-amino acid, (Z)-3-aminoprop-2-enoic acid, has been introduced into peptide foldamers through a one-pot chemical coupling, based on Pd/Cu-catalyzed olefin oxidative amidation, between two peptide segments carrying, respectively, a -Gly-NH2 residue at the C-terminus and an acryloyl group at the N-terminus. Reversible conversion between the Z and E configurations of the 3-aminoprop-2-enoic linkage was achieved photochemically. A crystallographic analysis on two model compounds shed light on the consequences, in terms of 3D structure and self-association properties, brought about by the different configuration of the unsaturated linkage. As a proof of concept, E–Z photoisomerization of a 3-aminoprop-2-enoic acid residue, inserted as the junction between two conformationally distinct peptide domains (one helical while the other β-sheet promoter), allowed supramolecular self-association to be reversibly turned on/off. Finally, we developed a versatile synthetic approach suitable for the stepwise incorporation of multiple, even consecutive, units of the simplest Cα,β-unsaturated β-amino acid, [(E/Z)-3-aminoprop-2-enoic acid] in peptide-based foldamers.