Participation of non-aminoisobutyric acid (Aib) residues in the 3₁₀helical conformation of Aib-rich foldamers: a solid state study

Abstract

The solid state conformational preferences of a series of 2-aminoisobutyric acid (Aib) foldamers bearing a single N-terminal tertiary amino acid (Cbz-L-phenylalanine (Cbz-L-Phe)) have been investigated by X-ray crystallography. The type of b-turn present at the N-terminus and the global screw-sense preferences of the Aib foldamers were determined by analysis of intramolecular hydrogen-bonds and peptide torsion angles. The contrasting influence of a C-terminal ester or amide on the 3 10 helical conformation of the foldamers was established by identifying the hydrogen-bonding motifs adopted in the solid state. The ability of non-Aib achiral quaternary residues in the middle of the chain to stabilise the 3 10 helix was similarly confirmed. Combining these structural features, which promote the formation of consecutive i -i + 3 b-turns in Aib foldamers, permitted the formation of long chain oligomers in 3 10 helical conformations that extend over 21 Å.

Helical peptaibol mimics are better ionophores when racemic than when enantiopure

“…The lower solubility of the racemates allowed crystals suitable for X-ray crystallography to be obtained for (rac)-1 (described previously 22 ) and (rac)-2; conditions to crystallise the enantiopure analogues were not found. Indeed, Huc and co-workers have used this increased propensity of racemic mixtures to crystallise to elucidate the structure of helical aromatic oligoamide foldamers.…”

“…Columns of opposite screw sense interact in a side-by-side antiparallel fashion. The crystal structure of (rac)-1 was analogous, 22 with columns of oligomers of the same screw sense linked by intermolecular head-to-tail hydrogen bonds, but with intermolecular π-π interactions between antiparallel columns. 25 To assess the ability of (S)-1, (rac)-1, (S)-2 and (rac)-2 to transport small ions through bilayers, we chose the phospholipid vesicle-based 8-hydroxypyrenetrisulfonate (HPTS) assay, using EYPC/cholesterol (4 : 1) vesicles with an interior pH of 7.4 and an exterior pH of 8.4.…”

Constructing synthetic-protein assemblies from de novo designed 310 helices

“…One group of natural peptides do commonly adopt 3 10 -helical conformations; namely, the membrane-active fungal metabolites known as the peptaibols 16,17 . These short peptides are rich in -disubstituted amino acids, in particular α-aminoisobutyric acid (Aib, U) [18][19][20][21][22][23][24] , which favour tighter helical turns characteristic of 3 10 helices [25][26][27][28] . However, the formation of 3 10 helices appears to fall off with lengths >9 residues, where -helix formation becomes favoured 29 .…”

Insight into the Mechanism of Action and Peptide‐Membrane Interactions of Aib‐Rich Peptides: Multitechnique Experimental and Theoretical Analysis

“…Studies in solution have demonstrated that Aib foldamers weakly self‐associate in chloroform solution, a solvent that is often assumed to mimic the membrane environment [6,26] . X‐ray investigations on the racemic mixtures of both 1 and 2 showed that in the solid state the peptides adopt a 3 10 helical conformation [18,27] . 8‐Hydroxypyrenetrisulfonate (HPTS) studies of the ionophoric activity of the peptide 1 in EYPC/cholesterol vesicles showed that at concentrations of 60 μM (25 : 2 lipid/peptide), the peptide allowed the leakage of ions and dye through the membrane without disrupting it.…”