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

Abstract

Helical α-aminoisobutyric acid (Aib) foldamers show great potential as devices for the communication of conformational information across phospholipid bilayers, but determining their conformation in bilayers remains a challenge. In the present study, Raman, Raman optical activity (ROA), infrared (IR) and vibrational circular dichroism (VCD) spectroscopies have been used to analyze the conformational preferences of Aib foldamers in solution and when interacting with bilayers. A 3 -helix marker band at 1665-1668 cm in Raman spectra was used to show that net helical content increased strongly with oligomer length. ROA and VCD spectra of chiral Aib foldamers provided the chiroptical signature for both left- and right-handed 3 -helices in organic solvents, with VCD establishing that foldamer screw-sense was preserved when the foldamers became embedded within bilayers. However, the population distribution between different secondary structures was perturbed by the chiral phospholipid. These studies indicate that ROA and VCD spectroscopies are valuable tools for the study of biomimetic structures, such as artificial signal transduction molecules, in phospholipid bilayers.

Bis-pyrene probes of foldamer conformation in solution and in phospholipid bilayers

“…This change is ascribed to perturbation of the response from the reporter rather than a change in the screw-sense of the foldamer. 27 The sensitivity ratio for foldamers 29 , 30 , 35–38 in bilayers was therefore below 1. Inversion of the S R value for ( S , S -BisPyrEt)NHAc-terminated foldamers 37 and 38 in bilayers (1/ S R = 1.3) allows meaningful comparison to the S R values for 37 and 38 in organic solution ( S R = 2.7) and reveals a reduced sensitivity to conformational change when in bilayers.…”

“… 35 Recent vibrational circular dichroism studies of enantiomeric Aib foldamers embedded in phospholipid bilayers hinted that phospholipid chirality may produce diastereoisomeric conformations. 27 Therefore the availability of two pairs of enantiomeric foldamers bearing bis(pyrene) reporters ( 38 and 49 ; 43 and 47 ) offers a unique opportunity to observe chiral induction due to the phospholipids that constitute the bilayer.…”

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

“…Raman and ROA : Previous ROA and VCD studies of peptides ( S )‐ 1 and ( R )‐ 1 have shown that these peptides adopt a partial 3 10 helix conformation in organic solvents like DMSO [8] . Figure 4 shows the Raman and ROA spectra of ( S )‐ 1 and ( R )‐ 1 embedded in vesicles.…”

“…A related class of peptide, comprising short synthetic Aib‐rich foldamers, also display membrane activity and have been employed to mimic membrane‐active molecules, including peptaibols [6,7] . The high content of Aib residues in these foldamers leads to the adoption of both P (right‐handed) and M (left‐handed) 3 10 helical conformations, and their high hydrophobicity is similar to that of the naturally occurring peptaibols [5,8–10] …”

“…The focus of this study was on the enantiomeric peptides ( R )‐ 1 and ( S )‐ 1 (Figure 1) which have a hydrophobic surface, an N‐terminal phenylalanine residue capped with a benzyloxycarbonyl (Cbz) group and a C terminus functionalized with a tert ‐butyl ester that introduces a Schellman‐like motif [24] . The N‐terminal Cbz group functions as an extra hydrogen bond acceptor that stabilizes the 3 10 helix conformation, and also has the potential to engage in π‐π stacking interactions [8,18,25] . We complemented the 1 enantiomers with ( R )‐ 2 , ( S )‐ 2 and ( S )‐ 4 , which each have an N‐terminal α‐methylvaline cap, and 3 which is achiral but long enough to span the hydrophobic region of a membrane [25,26] …”