Interrogating the potential of helical aromatic foldamers for protein recognition.

A biotinylated helical aromatic oligoamide foldamer equivalent in size to a 24mer peptide was designed without any prejudice other than to display various polar and hydrophobic side chains at its surface. It was synthesized on solid phase, its - and -helical conformers were separated by HPLC on a chiral stationary phase, and the solid state structure of a non-biotinylated analogue was elucidated by X-ray crystallography. Pull-down experiments from a yeast cell lysate using the foldamer as a bait followed by proteomic analysis revealed potential protein binding partners.

Directing the Self-Assembly of Aromatic Foldamer Helices using Acridine Appendages and Metal Coordination.

Folded molecules provide complex interaction interfaces amenable to sophisticated self-assembly motifs. Because of their high conformational stability, aromatic foldamers constitute suitable candidates for the rational elaboration of self-assembled architectures. Several multiturn helical aromatic oligoamides have been synthesized that possess arrays of acridine appendages pointing in one or two directions.

Oligo-Quinolylene-Vinylene Foldamers.

Quinoline based aromatic amide foldamers are known to adopt stable folded conformations. We have developed a synthetic approach to produce similar oligomers where all amide bonds, or part of them, have been replaced by an isosteric vinylene group. The results of solution and solid state structural studies show that oligomers exclusively containing vinylene linkages are not well folded, and adopt predominantly flat conformations.

Hybrid Sequences that Express both Aromatic Amide and α-Peptidic Folding Features.

Foldamers combining aliphatic and aromatic main-chain units often produce atypical structures that cannot easily be accessed from purely aromatic or aliphatic sequences. We report solid-state evidence that sequences comprising α-amino acids and quinoline-based monomers adopt conformations that combine the folding propensities of both components. Foldamers 2 and 3 having an XQQ repeat motif (X=α-amino acid, Q=quinoline) were synthesized.

Light-Controlled Conformational Switch of an Aromatic Oligoamide Foldamer.

An aromatic oligoamide sequence composed of a light-responsive diazaanthracene-based aromatic β-sheet flanked by two variable diameter helical segments was prepared. Structural investigations revealed that such oligomers adopt two distinct conformations: a canonical symmetrical conformation with the two helices stacked above and below the sheet, and an unanticipated unsymmetrical conformation in which one helix has flipped to directly stack with the first helix. Photoirradiation of the foldamer led to the quantitative, and thermally reversible, formation of a single photoproduct resulting from the [4+4] cycloaddition of two diazaanthracenes within the aromatic β-sheet.

Directional Threading and Sliding of a Dissymmetrical Foldamer Helix on Dissymmetrical Axles.

We have investigated the self-assembly of a dissymmetrical aromatic oligoamide helix on linear amido-carbamate rods. A dissymmetric sequence bearing two differentiated ends is able to wrap around dissymmetric dumbbell guest molecules. Structural and thermodynamic investigations allowed us to decipher the mode of binding of the helix that can bind specifically to the amide and carbamate groups of the rod.

Frustrated Helicity: Joining the Diverging Ends of a Stable Aromatic Amide Helix to Form a Fluxional Macrocycle.

Macrocyclization of a stable two-turn helical aromatic pentamide, that is, an object with diverging ends that are not prone to cyclization, was made possible by the transient introduction of disruptors of helicity in the form of acid-labile dimethoxybenzyl tertiary amide substituents. After removal of the helicity disruptors, NMR, X-ray crystallography, and computational studies show that the macrocycle possesses a strained structure that tries to gain as high a helical content as possible despite being cyclic. Two points of disruption of helicity remain, in particular a cis amide bond.

Single helically folded aromatic oligoamides that mimic the charge surface of double-stranded B-DNA.

Numerous essential biomolecular processes require the recognition of DNA surface features by proteins. Molecules mimicking these features could potentially act as decoys and interfere with pharmacologically or therapeutically relevant protein-DNA interactions. Although naturally occurring DNA-mimicking proteins have been described, synthetic tunable molecules that mimic the charge surface of double-stranded DNA are not known.