Light-mediated control of activity in a photosensitive foldamer that mimics an esterase.

We report a catalytic foldamer in which a fumaramide chromophore links a Ser residue to a helical domain that contains within its sequence the residues His and Asp. Photoisomerization of the fumaramide chromophore (with E geometry) to the corresponding maleamide (with Z geometry) brings together a 'catalytic triad' of Ser, His, and Asp, triggering esterase activity that is absent in the fumaramide isomer. The fumaramide/maleamide linker thus acts as a light-sensitive switchable cofactor for activation of catalytic activity in short foldamers.

Photoresponsive Prion-Mimic Foldamer to Induce Controlled Protein Aggregation.

Proteins reconfigure their 3D-structure, and consequently their function, under the control of specific molecular interactions that sense, process and transmit information from the surrounding environment. When this fundamental process is hampered, many pathologies occur as in the case of protein misfolding diseases. In this work, we follow the early steps of α-synuclein (aS) aggregation, a process associated with Parkinson's disease etiopathogenesis, that is promptly promoted by a light-mediated binding between the protein and a photoactive foldamer. The latter can switch between two conformations, one of which generates supramolecular fibrillar seeds that act as molecular templates able to induce a fast ß-sheet transition for aS monomers that successively undergo fibrillar polymerization. The proposed method represents a powerful tool to study protein aggregation relevant to misfolding diseases in a controlled and inducible system.

Effect on the Conformation of a Terminally Blocked, (E) ß,γ-Unsaturated δ-Amino Acid Residue Induced by Carbon Methylation.

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. In this study, 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) Cß═Cγ alkene unit. Specifically, we have examined by DFT calculations, X-ray diffraction in the crystalline state, and FT-IR absorption/NMR spectroscopies in solution the extended vs folded preferences of analogues of this prototype system either unmodified or possessing single or multiple methyl group substituents on each of its four -CH2-CH═CH-CH2- main-chain carbon atoms. 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.

Oligopeptide Helical Conformations Control Gold Nanoparticle Cross-Linking.

Peptide sequences functionalized with primary amines at the N- and C-terminus are able to induce the aggregation of gold nanoparticles in ethanol as a consequence of their folding into a helical conformation. Random coil peptides are unable to induce such an aggregation process. Aggregation can be monitored spectrophotometrically by following the shift of the surface plasmon resonance (SPR) band of the nanoparticles and is confirmed by transmission electron microscopy and dynamic light scattering analyses. Partial denaturation of the peptides results in diminished cross-linking ability. The helicity parameter θ222 /θ208 correlates fairly well with the shift of the SPR band to longer wavelengths, supporting the relationship between the amount of helical content of a peptide sequence and its ability to induce aggregation.

Tunable E- Z Photoisomerization in α,ß-Peptide Foldamers Featuring Multiple ( E/ Z)-3-Aminoprop-2-enoic Acid Units.

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. This work describes a versatile synthetic approach suitable for the stepwise incorporation of multiple, even consecutive, units of the simplest Cα,ß-unsaturated ß-amino acid, ( E/ Z)-3-aminoprop-2-enoic acid, in peptide-based foldamers. The properties of these, including photoinduced E/ Z isomerizations, were investigated.

Building Supramolecular DNA-Inspired Nanowires on Gold Surfaces: From 2D to 3D.

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. Film 1 consists of adenine linked to lipoic acid (Lipo-A) to covalently bind to the gold surface, and ZnTPP linked to a thymine (T-ZnTPP). Film 2 has an additional noncovalently linked layer: a helical undecapeptide analogue of the trichogin GA IV peptide, in which four glycines were replaced by four lysines to favor a helical conformation and reduce flexibility and the two extremities were functionalized with thymine and adenine to enable Lipo-A and T-ZnTPP binding, respectively. These films were characterized by electrochemical and spectroscopic techniques, and were very stable over time and when in contact with solution. Under illumination, they could generate current with higher efficiency than similar previously described systems.

Intrinsically Photoswitchable α/ß Peptides toward Two-State Foldamers.

A simple, unsaturated, E-Z photoisomerizable ß-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 ß-sheet promoter), allowed supramolecular self-association to be reversibly turned on/off.

Tuning morphological architectures generated through living supramolecular assembly of a helical foldamer end-capped with two complementary nucleobases.

Two appropriately functionalized nucleobases, thymine and adenine, have been covalently linked at the N- and C-termini, respectively, of two α-aminoisobutyric acid-rich helical peptide foldamers, aiming at driving self-assembly through complementary recognition. A crystal-state analysis (by X-ray diffraction) on the shorter, achiral foldamer 1 unambiguously shows that adeninethymine base pairing, through Watson-Crick intermolecular H-bonding, does take place between either end of each peptide molecule. In the crystals, π-stacking between base pairs is also observed. Evidence for time-dependent foldameroldamer associations for the longer, chiral foldamer 2 in solution is provided by circular dichroism measurements. The self-assembly of foldamer 2, through living supramolecular polymerization, eventually leads to the formation of twisted fibers. Such a supramolecular organization can be affected by addition of either pristine adenine or thymine, that acts as a "terminator" by selectively matching a pairing nucleobase at one end of the foldamer. The co-assembly of foldamer 2 with a porphyrin-derivatized thymine, under appropriate experimental conditions, leads to the formation of vesicles which, in turn, can be converted to the fiber morphology by changing the environmental polarity. Conversely, dendrimeric, star polymer-like microstructures are generated when the supramolecular assembly of foldamer 2 is seeded by adenine-capped gold nanoparticles.

Light-driven topochemical polymerization under organogel conditions of a symmetrical dipeptide-diacetylene system.

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. This is a typical reaction of ordered diacetylene moieties taking advantage from their organized packing mode resulting from fiber formation. 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. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd.

Helical Foldamers Incorporating Photoswitchable Residues for Light-Mediated Modulation of Conformational Preference.

An E unsaturated fumaramide linkage may be introduced into Aib peptide foldamer structures by standard coupling methods and photoisomerized to its Z (maleamide) isomer by irradiation with UV light. As a result of the photoisomerization, a new hydrogen-bonded contact becomes possible between the peptide domains located on either side of the unsaturated linkage. Using the fumaramide/maleamide linker to couple a chiral and an achiral fragment allows the change in hydrogen bond network to communicate a conformational preference, inducing a screw sense preference in the achiral domain of the maleamide-linked foldamers that is absent from the fumaramides. Evidence for the induced screw sense preference is provided by NMR and CD, and also by the turning on by light of the diastereoselectivity of a peptide chain extension reaction. The fumaramide/maleamide linker thus acts as a "conformational photodiode" that conducts stereochemical information as a result of irradiation by UV light.