Bimodal Use of Chiral α-Trifluoromethylalanine in Aib Foldamers: Study of the Position Impact Towards the Helical Screw-Sense Preference.

Oligomers of the achiral α-aminoisobutyric acid (Aib) adopt a 310 helical conformation in which the screw-sense preference can be controlled by a single chiral residue. The use of the fluorinated residue α-Trifluoromethylalanine (α-TfmAla) revealed a unique way to both induce and measure the screw-sense preference of such oligomers acting as 19F NMR probe. This work proposes a systematic study of the effect of this fluorinated chiral inducer on the helical screw-sense preference of poly-Aib oligomers. The impact of the position of the fluorinated residue into pentamers (N-terminal, central or C-terminal) as well as the nature of the C-terminal capping of the peptides was thoroughly studied in light of complete structural analysis. A deeper understanding of the fluorine effect was achieved confirming the unique ability of α-TfmAla as a helical screw-sense controller.

Dual, Photo-Responsive and Redox-Active Supramolecular Foldamers.

We report on dual, light-responsive and redox-active foldamers that demonstrate reversible and robust stimuli-induced behaviour. Herein, UV/Vis, 1H NMR and circular dichroism (CD) spectroscopy and cyclic voltammetry have been used to establish the reversibility and highly robust nature of the light- and redox-driven behaviour of these new foldamers with minimal levels of fatigue observed even upon multiple cyclic treatments with irradiative/non-irradiative and oxidative/reductive conditions. This proof-of-concept work paves the way towards the creation of novel stimuli-responsive foldamers of increasing sophistication capable of demonstrating reversible and robust responses to multiple distinct stimuli.

Visible-Light Driven Control Over Triply and Quadruply Hydrogen-Bonded Supramolecular Assemblies.

Supramolecular polymers offer tremendous potential to produce new "smart" materials, however, there remains a need to develop systems that are responsive to external stimuli. In this work, visible-light responsive hydrogen-bonded supramolecular polymers comprising photoresponsive supramolecular synthons (I-III) consisting of two hydrogen bonding motifs (HBMs) connected by a central ortho-tetrafluorinated azobenzene have been characterized by DOSY NMR and viscometry. Comparison of different hydrogen-bonding motifs reveals that assembly in the low and high concentration regimes is strongly influenced by the strength of association between the HBMs. I, Incorporating a triply hydrogen-bonded heterodimer, was found to exhibit concentration dependent switching between a monomeric pseudo-cycle and supramolecular oligomer through intermolecular hydrogen bonding interactions between the HBMs. II, Based on the same photoresponsive scaffold, and incorporating a quadruply hydrogen-bonded homodimer was found to form a supramolecular polymer which was dependent upon the ring-chain equilibrium and thus dependent upon both concentration and photochemical stimulus. Finally, III, incorporating a quadruply hydrogen-bonded heterodimer represents the first photoswitchable AB type hydrogen-bonded supramolecular polymer. Depending on the concentration and photostationary state, four different assemblies dominate for both monomers II and III, demonstrating the ability to control supramolecular assembly and physical properties triggered by light.

Controlling the Helical Pitch of Foldamers Through Terminal Functionality: A Solid State Study.

Developing new methods to control the size and shape of the helical structures adopted by foldamers is highly important as the secondary structure displayed by these supramolecular scaffolds often dictates their activity and function. Herein, we report on a systematic study demonstrating that the helical pitch of ortho-azobenzene/2,6-pyridyldicarboamide foldamers can be readily controlled through the nature of the terminal functionality. Remarkably, simply through varying the end group of the foldamer, and without modifying any other structural features of the scaffold, the helical pitch can be over doubled in magnitude (from 3.4 Å to 7.3 Å). Additionally, crystallographic analysis of a library ten foldamers has identified general trends in the influence of a range of terminal functionalities, including carboxylbenzyl (Cbz), diphenylcarbamyl (N(Ph)2), ferrocene (Fc) and tert-butyloxycarbonyl (Boc), in controlling the folding behaviour of these supramolecular scaffolds. These studies could prove useful in the future development of functional foldamers which adopt specific sizes and shapes.

Enhancing the Features of DNA Mimic Foldamers for Structural Investigations.

DNA mimic foldamers based on aromatic oligoamide helices bearing anionic phosphonate side chains have been shown to bind to DNA-binding proteins sometimes orders of magnitude better than DNA itself. Here, we introduce new features in the DNA mimic foldamers to facilitate structural investigations of their interactions with proteins. Thirteen new foldamer sequences have been synthesized and characterized using NMR, circular dichroism, molecular modeling, and X-ray crystallography. The results show that foldamer helix handedness can be quantitatively biased by means of a single stereogenic center, that the foldamer structure can be made C2-symmetrical as in palindromic B-DNA sequences, and that associations between foldamer helices can be promoted utilizing dedicated C-terminal residues that act as sticky ends in B-DNA structures.

From Double-Stranded Helicates to Abiotic Double Helical Supramolecular Assemblies.

The folding of oligomeric strands is the method that nature has selected to generate ordered assemblies presenting spectacular functions. In the purpose to mimic these biomacro-molecules and extend their properties and functions, chemists make important efforts to prepare artificial secondary, tertiary, and even quarternary structures based on folded abiotic backbones. A large variety of oligomers and polymers, encoded with chemical informations, were designed, synthesized and characterized, and the establishment of non-covalent interactions lead to complex and functional supramolecular architectures resulting from a spontaneous self-assembly process. The association of comple-mentary molecular strands into double helical structures is a common structural pattern of nucleic acids and proteins, so the synthesis of bio-inspired double helices has emerged as an important subject. In recent years, a number of synthetic oligo-mers have been reported to form stable double helices and it was shown that the equilibrium between single and double helices can be controlled via different stimuli like the modification of the solvent or the temperature. This kind of structure presents highly interesting functions, such as molecular recognition within the cavity of double helices, and some other potential applications will emerge in the future.

Benzoselenadiazole-Functionalized H-Bonded Arylamide Foldamers: Solvent-Responsive Properties and Helix Self-Assembly Directed by Chalcogen Bonding in Solid State.

In this study, a series of H-bonded arylamide foldamers bearing benzoselenadiazole ends with solvent-responsive properties have been synthesized. In dichloromethane or dimethyl sulfoxide solvents, the molecules exhibit meniscus or linear structures, respectively, which can be attributed to the unique intramolecular hydrogen bonding behavior evidenced by 1D 1H NMR and 2D NOESY spectra. UV-vis spectroscopy experiments show that the absorption wavelength of H-bonded arylamide foldamers are significantly red-shifted due to the presence of benzoselenadiazole group. In addition, the crystal structures reveal that effective intermolecular dual Se ⋅ ⋅ ⋅ N interactions between benzoselenadiazole groups induce further assembly of the monomers. Remarkably, supramolecular linear and double helices structures are constructed under the synergistic induction of intramolecular hydrogen bonding and intermolecular chalcogen bonding. Additionally, 2D DOSY diffusion spectra and theoretical modelling based on density functional theory (DFT) are performed to explore the persistence of intermolecular Se ⋅ ⋅ ⋅ N interactions beyond the crystalline state.

Exploring helix structures of γ-peptides based on 2-(aminomethyl)cyclopentanecarboxylic acid.

Conformational search and density functional theory calculations were performed to explore the preferences of helical structures for chiro-specific oligo-γ-peptides of 2-(aminomethyl)cyclopentanecarboxylic acid (γAmc5) with a cyclopentyl constraint on the Cα-Cß bond in solution. The dimer and tetramer of γAmc5 (1) with homochiral (1S, 2S) configurations exhibited a strong preference for the 9-membered helix foldamer in solution, except for the tetramer in water. However, the oligomers of γAmc5 (1) longer than tetramer preferentially adopted a right-handed (P)-2.614-helix (H1-14) as the peptide sequence becomes longer and as solvent polarity increases. The high stabilities for H1-14 foldamers of γAmc5 (1) in solution were ascribed to the favored solvation free energies. The calculated mean backbone torsion angles for H1-14 helix foldamers of γAmc5 (1) were similar to those calculated for oligomers of other γ-residues with cyclopentane or cyclohexane rings. However, the substitution of cyclopentane constraints on the Cα-Cß bond of the γAmc5 (1) residue resulted in different conformational preferences and/or handedness of helix foldamers. In particular, the pyrrolidine-substituted analogs of the H1-14 foldamers of γAmc5 (1) with adjacent amine diads substituted at a proximal distance are expected to be potential catalysts for the crossed aldol condensation in nonpolar and polar solvents.

Reaction, Recognition, Relay: Anhydride Hydrolysis Reported by Conformationally Responsive Fluorinated Foldamers in Micelles.

Natural membrane receptors are proteins that can report on changes in the concentration of external chemical messengers. Messenger binding to a receptor produces conformational changes that are relayed through the membrane into the cell; this information allows cells to adapt to changes in their environment. Artificial membrane receptors (R)-1 and (S)-1 are helical α-aminoisobutyric acid (Aib) foldamers that replicate key parts of this information relay. Solution-phase 19F NMR spectroscopy of zinc(II)-capped receptor 1, either in organic solvent or in membrane-mimetic micelles, showed messenger binding produced an enrichment of either left- or right-handed screw-sense; the chirality of the bound messenger was relayed to the other receptor terminus. Furthermore, in situ production of a chemical messenger in the external aqueous environment could be detected in real-time by a racemic mixture of receptor 1 in micelles. The hydrolysis of insoluble anhydrides produced carboxylate in the aqueous phase, which bound to the receptors and gave a distinct 19F NMR output from inside the hydrophobic region of the micelles.

Light- and Temperature-Controlled Hybridization, Chiral Induction and Handedness of Helical Foldamers.

Helical foldamers have attracted much attention over the last decades given their resemblance to certain biomacromolecules and their potential in domains as different as pharmaceutics, catalysis and photonics. Various research groups have successfully controlled the right- or left- handedness of these oligomers by introducing stereogenic centers through covalent or non-covalent chemistry. However, developing helical structures whose handedness can be reversibly switched remains a major challenge for chemists. To date, such an achievement has been reported with light-responsive single-stranded foldamers only. Herein, we demonstrate that grafting a unidirectional motor onto foldamer strands constitutes a relevant strategy to i) control the single or double helical state of a foldamer, ii) switch on the chiral induction process from the motor to the helical strands and iii) select the handedness of double helical structures through photochemical and thermal stimulations.

Design of Chiral ß-Double Helices from γ-Peptide Foldamers.

Chirality is ubiquitous in nature, and homochirality is manifested in many biomolecules. Although ß-double helices are rare in peptides and proteins, they consist of alternating L- and D-amino acids. No peptide double helices with homochiral amino acids have been observed. Here, we report chiral ß-double helices constructed from γ-peptides consisting of alternating achiral (E)-α,ß-unsaturated 4,4-dimethyl γ-amino acids and chiral (E)-α,ß-unsaturated γ-amino acids in both single crystals and in solution. The two independent strands of the same peptide intertwine to form a ß-double helix structure, and it is stabilized by inter-strand hydrogen bonds. The peptides with chiral (E)-α,ß-unsaturated γ-amino acids derived from α-L-amino acids adopt a (P)-ß-double helix, whereas peptides consisting of (E)-α,ß-unsaturated γ-amino acids derived from α-D-amino acids adopt an (M)-ß-double helix conformation. The circular dichroism (CD) signature of the (P) and (M)-ß-double helices and the stability of these peptides at higher temperatures were examined. Furthermore, ion transport studies suggested that these peptides transport ions across membranes. Even though the structural analogy suggests that these new ß-double helices are structurally different from those of the α-peptide ß-double helices, they retain ion transport activity. The results reported here may open new avenues in the design of functional foldamers.

Foldaxane-Based Switchable [c2]Daisy Chains.

Artificial molecular muscles are highly attractive in the field of molecular machinery due to their unique properties of contraction and stretching motion. However, the synthesis of molecular muscles poses formidable challenges as it is hindered by undesirable yields and poor selectivity. Herein, we present a procedure for the dynamic assembly of foldaxane-based [c2]daisy chains, wherein the hermaphroditic sequences consisting of aromatic helices and peptide rods are interlocked through inter-strand hydrogen-bonding interactions. The binding complementarity facilitates a selective and efficient assembly of [c2]daisy chain structures, inhibiting the creation of by-products. Introducing multiple recognition sites confers the system with contraction and stretching motion actuated by chemical stimuli. The rate of this muscle-like motion is calculated to be 0.8 s-1, which is 107 times faster than that of complex dissociation.

Heterochiral π-Stacking Dimerization of Helical Secondary Structures with Emerging Supramolecular Chirality.

A specific interface mode type was observed between helical secondary structures, in which a left-handed (M) helix binds specifically to a right-handed (P) helix along the helical axis, leading to the formation of discrete heterochiral helical dimers. Moreover, a concealed supramolecular chirality within the meso-supramolecular dimers was unexpectedly discovered by chiral induction, and was further underpinned by covalent meso-helix structures.

Stimuli-Responsive Molecular Duplexes Displaying Duplex-to-Duplex Switching.

Synthetic duplexes with high stabilities have promising potential for mimicking biomolecular functions and developing supramolecular smart materials. Herein, we describe the synthesis and stimuli-responsive properties of molecular duplexes derived from indolocarbazole-pyridine (I-P) oligomers. These duplexes adopt nonclassical helical structures, stabilized by I-P hydrogen-bonding pairs in anhydrous chlorinated solvents. Notably, the longest duplex 62 (11-mer)2 displays remarkable stability, forming twenty hydrogen bonds; its exchange energy barrier was determined to be ΔG≠=22.0 kcal ⋅ mol-1 at 75 °C in anhydrous (CDCl2)2. Upon the addition of water, a hydrated duplex 62 (11-mer)2⊃10H2O was formed, with one water molecule inserted between each I-P hydrogen-bonding pair. The Hill coefficient (n) for this process is 6.1, demonstrating extremely positive cooperativity. Conversely, the hydrated duplex 62 (11-mer)2⊃10H2O was completely converted into the original anhydrous duplex 62 (11-mer)2 when the temperature was increased. Interconversion between these two distinct duplexes can be repeatedly carried out by varying the temperature. Furthermore, reversible switching between hetero-duplexes and homo-duplexes was also demonstrated by controlling the temperature, with concomitant changes in the characteristic emission signals.

Cascading Macrocycle and Helix Motions in a Foldarotaxane Molecular Shuttle.

The design of a dynamically assembled foldarotaxane was envisioned with the aim of operating as a two cascading trigger-based molecular shuttle. Under acidic conditions, both the macrocycle and helix were localized around their respective best molecular stations because they are far enough from each other not to alter the stability of complexes. The pH-dependent localization of the macrocycle along the encircled axle allowed us to modulate the association between the helical foldamer and its sites of interaction on the axle. Under kinetic control-at low concentration and room temperature-when the foldarotaxane supramolecular architecture is kinetically stable, the pH-responsive translation of the macrocycle along the thread triggered the gliding of the helix away from its initial best station. At higher concentration-when helix assembly/disassembly process is accelerated-the system reached the equilibrium state. A new foldarotaxane isomer then appeared through the change of the relative position of the helix and macrocycle along the thread. In this isomer, the helix segregated the macrocycle away from its best station. The fine control of the kinetic and thermodynamic processes, combined with the control of pH, allowed the reciprocal segregation of the helix or the ring away from their respective best sites of interaction.

'Invisible' Molecular Dynamics Revealed for a Conformationally Chiral π-Stacked Perylene Bisimide Foldamer.

Whilst energetic and kinetic aspects of folding processes are meanwhile well understood for natural biomacromolecules, the folding dynamics in so far studied artificial foldamer counterparts remain largely unexplored. This is due to the low energy barriers between their conformational isomers that make the dynamic processes undetectable with conventional methods such as UV/vis absorption, fluorescence, and NMR spectroscopy, making such processes 'invisible'. Here we present an asymmetric perylene bisimide dimer (bis-PBI 1) that possesses conformational chirality in its folded state. Owing to the large interconversion barrier (≥ 116 kJ mol-1), four stereoisomers could be separated and isolated. Since the interconversion between these stereoisomers requires the foldamer to first open and then to re-fold, the transformation of one stereoisomer into others allowed us to 'visualize' the dynamics of folding with time and determine its lifetimes and the energetic barriers associated with the folding process. Supported by quantum chemical calculations, we identified the open structure to be only a fleeting metastable state of higher energy. Our experimental observation of the kinetics associated with the molecular dynamics in the PBI foldamer advances the fundamental understanding of folding in synthetic foldamers and paves the way for the design of smart functional materials.

Synthesis and Structural Investigation of Foldamer-Based Iodine-Supported Artificial Glycosidases.

Glycosidases are a type of enzyme that hydrolytically cleave carbohydrates and form glycans for biologically important processes. The inadequacies of glycosidases or their genetic abnormalities are responsible for various diseases. Thus, the development of glycosidase mimetics is of great importance. We have designed and synthesized an enzyme mimetic containing l-phenylalanine, α-aminoisobutyric acid (Aib), l-leucine, and m-Nifedipine. From X-ray crystallography, the foldamer adopts a ß-hairpin conformation stabilized by two 10-member and one 18-member NH⋅⋅⋅O=C hydrogen bonds. Moreover, the foldamer was found to be highly efficient in hydrolysing ethers and glycosides in the presence of iodine at room temperature. Further, X-ray analysis shows the backbone conformation of the enzyme mimetic to be almost unchanged after the glycosidase reaction. This is the first example of iodine-supported artificial glycosidase activity with an enzyme mimic at ambient conditions.

Foldamer Nanotubes Mediated Label-Free Detection of Protein-Small Molecule Interactions.

Development of miniaturized lab-on-chip devices for the detection of rapid and specific small molecule-protein binding interactions at very low concentrations holds significant importance in drug discovery and biomedical applications. Here, the label-free detection of small molecule-protein interactions is reported on the surface functionalizable nanotubes of α,γ-hybrid peptide helical foldamers using nanoscale capacitance and impedance spectroscopy. The 12-helix conformation of the α,γ-hybrid peptide observed in the single crystals, self-assembled into nanotubes in an aqueous environment with exposed cysteine thiols for small molecule conjugation. The binding of streptavidin to the covalently linked biotin on the surface of nanotubes was detected at the picomolar concentrations. No change in the capacitance and impedance were observed in the absence of either immobilized biotin or protein streptavidin. The functionalizable hybrid peptide nanotubes reported here pave the way for the label-free detection of various small molecule protein interactions at very low concentrations.

Anion Tuned Structural Modulation and Nonlinear Optical Effects of Metal-Ion Directed 310 -Helix Networks.

Metals play an important role in the structure and functions of various proteins. The combination of metal ions and peptides have been emerging as an attractive field to create advanced structures and biomaterials. Here, we are reporting the anion-influenced, silver ion coordinated diverse networks of designed short tripeptide 310 -helices with terminal pyridyl groups. The short peptides adopted classical right-handed, left-handed and 310 EL -helical conformations in the presence of different silver salts. The peptides have displayed conformational flexibility to accommodate different sizes and interactions of anions to yield a variety of metal-coordinated networks. The complexes of metal ions and peptides have shown different porous networks, right- and left-handed helical polymers, transformation of helix into superhelix and 2 : 2 metal-peptide macrocycles. Further, the metal-peptide crystals with inherent dipoles of helical peptides gave striking second harmonic generation response. The optical energy upconversion from NIR to red and green light is demonstrated. Overall, we have shown the utilization of short 310 -helices for the construction of diverse metal-coordinated helical networks and notable non-linear optical effects.

Introducing Aliphatic Fluoropeptides: Perspectives on Folding Properties, Membrane Partition and Proteolytic Stability.

A de novo designed class of peptide-based fluoropolymers composed of fluorinated aliphatic amino acids as main components is reported. Structural characterization provided insights into fluorine-induced alterations on ß-strand to α-helix transition upon an increase in SDS content and revealed the unique formation of PPII structures for trifluorinated fluoropeptides. A combination of circular dichroism, fluorescence-based leaking assays and surface enhanced infrared absorption spectroscopy served to examine the insertion and folding processes into unilamellar vesicles. While partitioning into lipid bilayers, the degree of fluorination conducts a decrease in α-helical content. Furthermore, this study comprises a report on the proteolytic stability of peptides exclusively built up by fluorinated amino acids and proved all sequences to be enzymatically degradable despite the degree of fluorination. Herein presented fluoropeptides as well as the distinctive properties of these artificial and polyfluorinated foldamers with enzyme-degradable features will play a crucial role in the future development of fluorinated peptide-based biomaterials.