Folding and Assembly of Short α, ß, γ-Hybrid Peptides: Minor Variations in Sequence and Drastic Differences in Higher-Level Structures.

Multilevel protein structures typically involve polypeptides of sufficient lengths. Here we report the folding and assembly of seven short tetrapeptides sharing the same types of α-, ß-, and aromatic γ-amino acid residues. These are two sets of hybrid peptides, with three members in one set and four in the other, having complementary hydrogen-bonding sequences that were hypothesized to pair into linear H-bonded duplexes. However, instead of undergoing the anticipated pairing, the initially examined three oligomers, 1 and 2a or 2b, differing only in their central αß hybrid dipeptide sequence, do not associate with each other and exhibit distinctly different folding behavior. Experiments based on NMR and mass spectrometry, along with computational studies and systematic inference, reveal that oligomer 1 folds into an expanded ß-turn containing an unusual hybrid α/ß-amino acid sequence composed of glycine and ß-alanine, two α- and ß-amino acid residues that are conformationally most flexible, and peptides 2a and 2b adopt a noncanonical, extended helical conformation and dimerize into double helices undergoing rapid conformational exchange or helix inversion. The different central dipeptide sequences, αß vs ßα, result in drastically different intramolecular H-bonding patterns that are responsible for the observed folding behavior of 1 and 2. The revealed turn and double helix have few natural or synthetic counterparts, and provide novel and unique folding prototypes based on which chiral α- and ß-amino acids are incorporated. The resultant derivatives 1a, 1b, 2c, and 2d follow the same folding and assembling behavior and demonstrate the generality of this system with the formation of expanded ß-turns and double helices with enhanced folding stabilities, hampered helix inversion, as well as defined and dominant helical sense. This work has demonstrated the unique capability of synthetic foldamers in generating structures with fascinating folding and assembling behavior. The revealed systems offer ample opportunity for further structural optimization and applications.

Enforced Tubular Assembly of Electronically Different Hexakis(m-Phenylene Ethynylene) Macrocycles: Persistent Columnar Stacking Driven by Multiple Hydrogen-Bonding Interactions.

Hexakis(m-phenylene ethynylene) (m-PE) macrocycles 1-4, sharing the same hydrogen-bonding side chains but having backbones of different electronic properties, are designed to probe the effectiveness of multiple H-bonding interactions in enforcing columnar assemblies. 1H NMR, absorption, fluorescence, and circular dichroism (CD) spectroscopy indicate that, compared with analogous macrocycles that self-associate based on aromatic stacking which is highly sensitive to the electronic nature of the macrocyclic backbones, macrocycles 1-4 all exhibit strong aggregation down to the micromolar (µM) concentrations in nonpolar solvents. Increasing solvent polarity quickly weakens aggregation. In THF and DMF, the macrocycles exist as free molecules. The observed solvent effects, along with the behavior of 5-F6 that cannot self-associate via H-bonding, confirm that H-bonding plays the dominating role in driving the self-association of 1-4. The backbone electronic nature does not change the self-assembling pattern common to 1-4. Fluorescence and CD spectra confirm that macrocycles 1-4 assemble anisotropically, forming helical stacks in which adjacent molecules undergo relative rotation to place individual benzene residues in the favorable offset fashion. Columnar alignment of 1-4 is confirmed by atomic force microscopy (AFM), which resolves single tubes consisting of stacked macrocycles. In addition, macrocycles with backbones of different electronic properties are found to undergo heteroassociation, forming hybrid nanotubes. This study has demonstrated the generality of enforcing the alignment of shape-persistent macrocycles, which represents an invaluable addition to the small number of known tubular stacks capable of accommodating structurally varied molecular components and provides self-assembling nanotubes with inner pores allowing ready structural and functional modification.

Effects of Oligomer Length, Solvents, and Temperature on the Self-Association of Aromatic Oligoamide Foldamers.

The effects of oligomer length, solvent, and temperature on the self-association of stably folded short aromatic oligoamide are probed. With large flat surfaces, these aromatic oligoamides undergo stacking interaction with strength that increases nonlinearly with oligomer lengths. Opposite to typical aromatic stacking, the stacking of these molecules is enhanced in solvents of low polarity, but it is greatly weakened in polar solvents, especially those with hydrogen bond donors, and it is very sensitive to changes in temperature.

Helical Folding of Meta-Connected Aromatic Oligoureas.

Aromatic oligoureas composed of meta-linked residues bearing phenolic ether side chains are synthesized. The basic N,N'-diarylurea units adopt a trans,trans intramolecularly H-bonded conformation that is further strengthened by additional intermolecular H-bonding. Such basic units, in combination with meta-linked benzene residues, result in stably folded helical oligoureas in the highly polar DMF with up to four turns and with a small cylindrical inner pore that would be difficult to acquire.

Aromatic oligureas as hosts for anions and cations.

Aromatic oligoureas 3 and 4 have urea moieties engaging in weak intramolecular H-bonding that constrains their backbones. The shorter 3a and 3b are able to bind chloride and acetate but not their corresponding counterion. The longer 4 binds both an anion and its counterion with the same affinity.