Left-Handed Helical Preference in an Achiral Peptide Chain Is Induced by an l-Amino Acid in an N-Terminal Type II β-Turn

Abstract

Oligomers of the achiral amino acid Aib adopt helical conformations in which the screw-sense may be controlled by a single N-terminal residue. Using crystallographic and NMR techniques, we show that the left- or right-handed sense of helical induction arises from the nature of the β-turn at the N terminus: the tertiary amino acid L-Val induces a left-handed type II β-turn in both the solid state and in solution, while the corresponding quaternary amino acid L-α-methylvaline induces a right-handed type III β-turn.

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

“…A valuable comparison with foldamers ( R )‐ 7 and ( S )‐ 7 is provided by foldamers ( R )‐ 8 and ( S )‐ 9 , which have either one or two chiral α‐methylvaline (αMeVal) quaternary amino acid residues on the N‐terminus. Chiral quaternary amino acid residues at the N‐terminus produce a type III β‐turn and induce a helical screw sense opposite to tertiary amino acid controllers with the same configuration . Therefore capping with d ‐αMeVal, as found in ( R )‐ 8 , gives predominately the left‐handed 3 10 ‐helix, with an h.e.…”

“…However, adding a chiral cap, as in foldamers ( R )‐ 7 and ( S )‐ 7 , biases each equilibrium towards one helical screw sense and allows the foldamers to be detected using chiroptical spectroscopies. The chiral N‐terminal phenylalanine “controller” cap in enantiomeric foldamers ( S )‐ 7 and ( R )‐ 7 causes the foldamer body to preferably adopt either a left‐handed ( M ) helix (foldamer capped with Cbz( l ‐Phe)) or a right‐handed ( P ) helix (foldamer capped with Cbz( d ‐Phe)) in organic solvents . The extent of this bias is determined by the nature of the chiral capping group and can be quantified by using NMR spectroscopy to calculate the helical excess (h.e.…”

“…. For example, NMR spectroscopy studies in organic solvents have shown that chiral quaternary l ‐amino acids bearing two different substituents at the α‐carbon, such as l ‐α‐methylvaline, at the N‐terminus favor a right‐handed helix . In contrast, the opposite screw‐sense preference is found for tertiary residues, such as l ‐Phe, at the N‐terminus (Figure d) .…”

“…Thus, the VCD spectrum of ( S )‐ 8 (Cbz( l ‐αMeVal)Aib 4 O t Bu) shows a positive amide I couplet at 1653(+)/1683(−) and negative amide II band at 1520 cm −1 , possibly arising from the IR bands at 1663 and 1532 cm −1 , respectively (Figure c,d). Such a VCD pattern corresponds to right‐handed helix, while the mirror‐image VCD of ( R )‐ 8 (Cbz( d ‐αMeVal)Aib 4 O t Bu) corresponds to left‐handed helix; both observations are in agreement with x ‐ray crystallography and NMR spectroscopy studies . The inverse spectral relationship between foldamers capped with Phe and αMeVal of the same configuration confirms that VCD bands in the amide I and amide II regions are reporting on the conformation of the foldamer rather than the chirality of the cap.…”

Synthesis of Z‐Protected Aib‐ and Phe(2Me)‐Containing Pentapeptides and Their Crystal Structures

“…Val and Val(2Me): the hexapeptides Ac-L-Xaa-(Aib) 4 -Gly NH 2 and pentapeptides Ac-L-Xaa-(Aib) 4 -OR form left-handed helices with Xaa = Val but right-handed helices with Xaa = Val(2Me) [42]. The study of the influence of the type and the position of L-and D-amino acids on the helical screw sense of Aib-containing peptides is a topic of current interest (see, e.g., [43]).…”