Aromatic oligoamide macrocycles exhibit strong preference for highly directional association. Aggregation happens in both nonpolar and polar solvents but is weakened as solvent polarity increases. The strong, directional assembly is rationalized by the cooperative action of dipole-dipole and π-π stacking interactions, leading to long nanotubular assemblies that are confirmed by SEM, TEM, AFM, and XRD. The persistent nanotubular assemblies contain non-collapsible hydrophilic internal pores that mediate highly efficient ion transport observed with these macrocycles and serve as cylindrical sites for accommodating guests such as metal ions.

This Feature Article gives an account for a host of readily available foldamers and macrocycles with well-defined shapes and non-deformable cavities that appeared over the last decade. Efforts to create porous molecular structures have led to the establishment of an effective strategy for enforcing the folding of unnatural aromatic oligoamide strands based on an especially robust three-center (bifurcated) hydrogen-bonding interaction. Based on such a strategy, aromatic oligoamides adopting crescent and helical conformations that contain non-collapsible cavities of tunable diameters have been created. Extending the same folding principle to the preparation of aromatic polyamides that would adopt pore-containing helical conformation instead led to the discovery of a highly efficient, one-pot macrocyclization process. Such a one-pot macrocyclization process has been successfully applied to the preparation of macrocycles with aromatic amide, hydrazide, urea and other backbones. Mechanistic study indicates that the high efficiencies observed for the formation of these macrocycles are due to the folding of the corresponding uncyclized oligomeric precursors of the corresponding macrocycles. Oligoamide macrocycles, along with their uncyclized, cavity-containing counterparts, i.e., crescent oligoamides, bind guests such as guanidinium (G) and octylguanidinium (OG) ions with tunable selectivity. Recent studies revealed that these rigid macrocycles tend to engage in extraordinarily strong, directional aggregation, leading to nanotubular assemblies containing pores of fixed sizes. Consistent with the presence of self-assembling nanopores, oligoamide macrocycles were found to assemble into transmembrane channels with high conductance.

Rigid macrocycles 2, which share a hybrid backbone and the same set of side chains while having inner cavities with different inward-pointing functional groups, undergo similar nanotubular assembly as indicated by multiple techniques including (1)H NMR, fluorescence spectroscopy, and atomic force microscopy. The formation of tubular assemblies containing subnanometer pores is also attested by the different transmembrane ion-transport behavior observed for these macrocycles. Vesicle-based stopped-flow kinetic assay and single-channel electrophysiology with planar lipid bilayers show that the presence of an inward-pointing functional (X) group in the inner cavity of a macrocyclic building block exerts a major influence on the transmembrane ion-transporting preference of the corresponding self-assembling pore. Self-assembling pores with inward-pointing amino and methyl groups possess the surprising and remarkable capability of rejecting protons but are conducive to transporting larger ions. The inward-pointing groups also resulted in transmembrane pores with a different extent of positive electrostatic potentials, leading to channels having different preferences for transporting chloride ion. Results from this work demonstrate that synthetic modification at the molecular level can profoundly impact the property of otherwise structurally persistent supramolecular assemblies, with both expected tunability and suprisingly unusual behavior.

A primary limitation to real-time imaging of metabolites and proteins has been the selective detection of biomolecules that have no naturally-occurring or stable molecular recognition counterparts. We present developments in the design of synthetic near-infrared fluorescent nanosensors based on the fluorescence modulation of single-walled carbon nanotubes (SWNT) with select sequences of surface-adsorbed N-substituted glycine peptoid polymers. We assess the stability of the peptoid-SWNT nanosensor candidates under variable ionic strengths, protease exposure, and cell culture media conditions, and find that the stability of peptoid-SWNTs depends on the composition and length of the peptoid polymer. From our library, we identify a peptoid-SWNT assembly that can selectively detect lectin protein wheat germ agglutinin (WGA) with a sensitivity comparable to the concentration of serum proteins. This WGA protein nanosensor is characterized with near-infrared spectroscopy and microscopy to study protein-nanosensor interaction parameters. To demonstrate the retention of nanosensor-bound protein activity, we show that WGA on the nanosensor produces an additional fluorescent signal modulation upon exposure to the lectin's conjugate sugars, suggesting the lectin protein selectively binds its target sugars through ternary molecular recognition interactions relayed to the nanosensor. Our results inform design considerations for developing synthetic molecular recognition elements by assembling peptoid polymers on SWNTs, and also demonstrate these assemblies can serve as optical nanosensors for lectin proteins and their target sugars. Together, these data suggest certain peptoid sequences can be assembled with SWNTs to serve as versatile optical probes to detect proteins and their molecular substrates.