Designing Foldamer–Foldamer Interactions in Solution: The Roles of Helix Length and Terminus Functionality in Promoting the Self‐Association of Aminoisobutyric Acid Oligomers

Abstract

The biological activity of antibiotic peptaibols has been linked to their ability to aggregate, but the structure-activity relationship for aggregation is not well understood. Herein, we report a systematic study of a class of synthetic helical oligomer (foldamer) composed of aminoisobutyric acid (Aib) residues, which mimic the folding behavior of peptaibols. NMR spectroscopic analysis was used to quantify the dimerization constants in solution, which showed hydrogen-bond donors at the N terminus promoted aggregation more effectively than similar modifications at the C terminus. Elongation of the peptide chain also favored aggregation. The geometry of aggregation in solution was investigated by means of titrations with [D6]DMSO and 2D NOE NMR spectroscopy, which allowed the NH protons most involved in intermolecular hydrogen bonds in solution to be identified. X-ray crystallography studies of two oligomers allowed a comparison of the inter- and intramolecular hydrogen-bonding interactions in the solid state and in solution and gave further insight into the geometry of foldamer-foldamer interactions. These solution-based and solid-state studies indicated that the preferred geometry for aggregation is through head-to-tail interactions between the N and C termini of adjacent Aib oligomers.

Optically Active Vibrational Spectroscopy of α‐Aminoisobutyric Acid Foldamers in Organic Solvents and Phospholipid Bilayers

“…Aib foldamers have a hydrophobic surface, which facilitates membrane insertion, so an organic solvent is needed to dissolve them. Chloroform, with a low dielectric constant (relative permittivity) of 4.81 and a dipole moment of 1.05 D, has often been used to mimic the low polarity found at the center of the bilayer . However, if sealed cells are either not available or not suitable, the high volatility of chloroform may be a drawback for performing measurements that may take many hours, such as ROA and VCD.…”

“…Chloroform,w ith al ow dielectric constant (relative permittivity) of 4.81 and ad ipole moment of 1.05 D, has often been used to mimic the low polarity found at the centero f the bilayer. [39] However,i fs ealed cells are either not available or not suitable, the high volatility of chloroform may be a drawback for performing measurements that may take many hours, such as ROA and VCD. In addition, chloroform vibrational bands can interferew ith those of the peptide.T here is also the potential for intermolecular aggregation of longerf oldamers at high concentrationst ypically required for ROA experiments (> 40 mg mL À1 ).…”

Helical peptaibol mimics are better ionophores when racemic than when enantiopure

“…15 Strong self-association of peptaibols in non-polar environments has been suggested to increase the tendency of these compounds to form self-assembled channels. 15,18 To model how these folded peptides might self-associate in a bilayer, changes in their 1 H NMR spectra were monitored as concentrated solutions in the apolar solvent CDCl 3 were progressively diluted. 19 However the concentration range studied for racemates (rac)-1 and (rac)-2 was limited by their lower solubility, as they had saturation concentrations (30 and 15 mM respectively) that were markedly lower than their enantiopure counterparts (150 and 75 mM respectively, e.g.…”

Molecular Recognition by Zn(II)‐Capped Dynamic Foldamers

“…Aggregation occurred between foldamers of same screw‐sense: both M and P Aib helical conformations are identified in the unit cell, but the Zn(II) metal center of a M helical conformation is found to preferentially interact with the glycinamide of a M helix and vice versa for P helices. The observation of interfoldamer interactions between relatively unfunctionalized foldamers in such a polar solvent suggests that chiral information could potentially be relayed between appropriately designed foldamers, providing complex systems that sense multiple analytes …”