Molecular torsion springs: alteration of helix curvature in frustrated tertiary folds.

The first abiotic foldamer tertiary structures have been recently reported in the form of aromatic helix-turn-helix motifs based on oligo-quinolinecarboxamides held together by intramolecular hydrogen bonds. Tertiary folds were predicted by computational modelling of the hydrogen-bonding interfaces between helices and later verified by X-ray crystallography. However, the prognosis of how the conformational preference inherent to each helix influences the tertiary structure warranted further investigation. Several new helix-turn-helix sequences were synthesised in which some hydrogen bonds have been removed. Contrary to expectations, this change did not strongly destabilise the tertiary folds. On closer inspection, a new crystal structure revealed that helices adopt their natural curvature when some hydrogen bonds are missing and undergo some spring torsion upon forming the said hydrogen bonds, thus potentially giving rise to a conformational frustration. This phenomenon sheds light on the aggregation behaviour of the helices when they are not linked by a turn unit.

Parallel Homochiral and Anti-Parallel Heterochiral Hydrogen-Bonding Interfaces in Multi-Helical Abiotic Foldamers.

A hydrogen-bonding interface between helical aromatic oligoamide foldamers has been designed to promote the folding of a helix-turn-helix motif with a head-to-tail arrangement of two helices of opposite handedness. This design complements an earlier helix-turn-helix motif with a head-to-head arrangement of two helices of identical handedness interface. The two motifs were shown to have comparable stability and were combined in a unimolecular tetra-helix fold constituting the largest abiotic tertiary structure to date.

Interplay of secondary and tertiary folding in abiotic foldamers.

The first true abiotic tertiary folded structures, i.e. at the exclusion of any aliphatic amino acid, have recently been introduced under the form of aromatic oligoamide helix-turn-helix foldamers stabilized by hydrogen bonds in organic solvents. We present an investigation of the interplay of secondary and tertiary folding and of some cooperative effects in these systems. A solid phase synthesis approach to the preparation of these sequences was developed to facilitate systematic variation. Flexible pyridine-based units were introduced in various proportions in replacement of more rigid quinoline-based units. Conformational behaviour was assessed in solution by NMR, in the solid state by X-ray crystallography, and computationally through molecular dynamics simulations. Altogether, our results demonstrate that tertiary folding stabilizes otherwise flexible secondary structures, and that the disruption of tertiary folds upon adding polar solvents follows different mechanisms depending on whether secondary structures are inherently stable or not. These findings constitute a solid basis on which to further increase the size and complexity of abiotic folded structures and to eventually orchestrate folding dynamics and responsiveness.

Improved synthesis of glycine, taurine and sulfate conjugated bile acids as reference compounds and internal standards for ESI-MS/MS urinary profiling of inborn errors of bile acid synthesis.

Bile acid synthesis defects are rare genetic disorders characterized by a failure to produce normal bile acids (BAs), and by an accumulation of unusual and intermediary cholanoids. Measurements of cholanoids in urine samples by mass spectrometry are a gold standard for the diagnosis of these diseases. In this work improved methods for the chemical synthesis of 30 BAs conjugated with glycine, taurine and sulfate were developed. Diethyl phosphorocyanidate (DEPC) and diphenyl phosphoryl azide (DPPA) were used as coupling reagents for glycine and taurine conjugation. Sulfated BAs were obtained by sulfur trioxide-triethylamine complex (SO3-TEA) as sulfating agent and thereafter conjugated with glycine and taurine. All products were characterized by NMR, IR spectroscopy and high resolution mass spectrometry (HRMS). The use of these compounds as internal standards allows an improved accuracy of both identification and quantification of urinary bile acids.

En route towards the peptide γ-helix: X-ray diffraction analyses and conformational energy calculations of Adm-rich short peptides.

We performed the solution-phase synthesis of a set of model peptides, including homo-oligomers, based on the 2-aminoadamantane-2-carboxylic acid (Adm) residue, an extremely bulky, highly lipophilic, tricyclic, achiral, Cα -tetrasubstituted α-amino acid. In particular, for the difficult peptide coupling reaction between two Adm residues, we took advantage of the Meldal's α-azidoacyl chloride approach. Most of the synthesized Adm peptides were characterized by single-crystal X-ray diffraction analyses. The results indicate a significant propensity for the Adm residue to adopt γ-turn and γ-turn-like conformations. Interestingly, we found that a -CO-(Adm)2 -NH- sequence is folded in the crystal state into a regular, incipient γ-helix, at variance with the behavior of all of the homo-dipeptides from Cα -tetrasubstituted α-amino acids already investigated, which tend to adopt either the ß-turn or the fully extended conformation. Our density functional theory conformational energy calculations on the terminally blocked homo-peptides (n = 2-8) fully confirmed the crystal-state data, strongly supporting the view that this rigid Cα -tetrasubstituted α-amino acid residue is largely the most effective building block for γ-helix induction, although to a limited length (anti-cooperative effect). Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd.

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.

A terminally protected dipeptide: from crystal structure and self-assembly, through co-assembly with carbon-based materials, to a ternary catalyst for reduction chemistry in water.

A terminally protected, hydrophobic dipeptide Boc-L-Cys(Me)-L-Leu-OMe (1) was synthesized and its 3D-structure was determined by single crystal X-ray diffraction analysis. This peptide is able to hierarchically self-assemble in a variety of superstructures, including hollow rods, ranging from the nano- to the macroscale, and organogels. In addition, 1 is able to drive fullerene (C60) or multiwalled carbon nanotubes (MWCNTs) in an organogel by co-assembling with them. A hybrid 1-C60­MWCNT organogel was prepared and converted (through a high vacuum-drying process) into a robust, high-volume, water insoluble, solid material where C60 is well dispersed over the entire superstructure. This ternary material was successfully tested as a catalyst for: (i) the reduction reaction of water-soluble azo compounds mediated by NaBH4 and UV-light with an overall performance remarkably better than that provided by C60 alone, and (ii) the NaBH4-mediated reduction of benzoic acid to benzyl alcohol. Our results suggest that the self-assembly properties of 1 might be related to the occurrence in its single crystal structure of a sixfold screw axis, a feature shared by most of the linear peptides known so far to give rise to nanotubes.

Synthesis and photochemical applications of processable polymers enclosing photoluminescent carbon quantum dots.

Herein, we propose convenient routes to produce hybrid-polymers that covalently enclosed, or confined, N-doped carbon quantum dots (CQDs). We focus our attention on polyamide, polyurea-urethane, polyester, and polymethylmetacrylate polymers, some of the most common resources used to create everyday materials. These hybrid materials can be easily prepared and processed to obtain macroscopic objects of different shapes, i.e., fibers, transparent sheets, and bulky forms, where the characteristic luminescence properties of the native N-doped CQDs are preserved. More importantly we explore the potential use of these hybrid composites to achieve photochemical reactions as those of photoreduction of silver ions to silver nanoparticles (under UV-light), the selective photo-oxidation of benzylalcohol to the benzaldehyde (under vis-light), and the photocatalytic generation of H2 (under UV-light).

Enhancement of the helical content and stability induced in a linear oligopeptide by an i, i+4 intramolecularly double stapled, overlapping, bicyclic [31, 22, 5]-(E)ene motif.

Two consecutive i, i+4 intramolecular, side chain-to-side chain, macrocyclizations of different type carried out on a preformed, partially helical peptide result in a largely predominant, double stapled, overlapping, bicyclic [31,22,5]-(E)ene motif. A detailed ECD and NMR conformational study revealed a significant enhancement of the original helical content and stability, accompanied by an increase of the α-helix amount over that of the 3(10)-helix.