Quantifying End‐to‐End Conformational Communication of Chirality through an Achiral Peptide Chain

Abstract

Helicity is a widespread characteristic of the secondary structure of peptides: those built of l-amino acids typically adopt right-handed helical structures, even when most of the chain is achiral. [1] Helical peptide motifs may be stabilized by the incorporation of quaternary amino acids such as Aib (aminoisobutyric acid), [2] and oligomers of Aib adopt racemic helical conformations. [3,4] Favored adoption of a left-or righthanded helix may be controlled by judicious distribution of chiral monomers along any polymer chain. [5] A bias towards one absolute sense of helicity may also arise from a terminal chiral residue bound covalently [6, 7] or noncovalently [8] to an otherwise achiral peptide chain. At the limit, absolute helicity (that is, a left-or right-handed helical preference) may be induced in an otherwise configurationally achiral oligomer by a single terminal amino acid. The work of Toniolo et al. (for short Aib n oligomers) [6] and of Inai et al. (for oligomers of Aib-D Z Phe (D Z Phe = (Z)-didehydrophenylalanine) [7,8] has shown that covalent or noncovalent attachment of a terminal chiral residue leads to a helicity preference [9] in at least part of the peptide structure, detectable by circular dichroism.What we now establish is how far the asymmetric influence of a terminal chiral residue can persist through a single isolated helical structure-in other words the fidelity with which a helical peptide built of achiral monomers can carry information about a terminal residue over ever increasing distances. Previous studies have used CD to detect helicity in the oligomer as a whole, but no information on asymmetry localized at the helix terminus can be gathered by this method. [10] As a helix of achiral monomers is lengthened, every achiral residue must carry a finite chance of helix inversion, leading to erosion of the asymmetric environment at the terminus of the growing oligomer. Using a simple spectroscopic technique, we have now evaluated the local asymmetry of a pair of geminal "reporter" 1 H nuclei at the C terminus of a peptide containing a single N-terminal chiral residue, and hence have quantified both the distance over which oligomers retain a helical preference in solution and the fidelity with which each achiral amino acid transmits a helical preference along the chain.The method relies on the observation by NMR spectroscopy of anisochronicity between two 1 H nuclei which are indistinguishable unless they find themselves in a chiral environment. In a helix built entirely of achiral monomers, and inverting rapidly on the NMR timescale, the two "reporter" nuclei are in fast exchange and must be isochronous. [11] If a remote chiral influence succeeds in inducing preferentially one absolute helicity in the oligomer, the symmetry of the local environment of the nuclei will be broken, rendering the diastereotopic nuclei anisochronous. Provided the chiral controller is located sufficiently far away to avoid direct interaction with the reporter nuclei, the degree of anisochronicity reflects a weig...

Induction of Unexpected Left‐Handed Helicity by an N‐Terminal L‐Amino Acid in an Otherwise Achiral Peptide Chain

“…[16] Switching the configuration of the chiral terminal residue switches the helical preference of the entire oligomer, [17] and the literature suggests [9] that in solution an lamino acid induces right-handed helicity in an achiral Aib n peptide chain. [18] Herein we report a combined NMR spectroscopy, circular dichroism (CD) spectroscopy, and computational study that shows that an oligo(Aib) 3 10 helix carrying an N-terminal lamino acid residue (specifically l-valine (l-Val), l-alanine (lAla) or l-phenylalanine (l-Phe)) adopts left-handed (M) helicity. Corresponding 3 10 helices carrying an N-terminal amethylated (quaternary) amino acid such as l-a-methylvaline (l-aMv) or l-isovaline (l-Iva) conversely adopt the expected right-handed (P) helicity.…”

“…[18] Herein we report a combined NMR spectroscopy, circular dichroism (CD) spectroscopy, and computational study that shows that an oligo(Aib) 3 10 helix carrying an N-terminal lamino acid residue (specifically l-valine (l-Val), l-alanine (lAla) or l-phenylalanine (l-Phe)) adopts left-handed (M) helicity. Corresponding 3 10 helices carrying an N-terminal amethylated (quaternary) amino acid such as l-a-methylvaline (l-aMv) or l-isovaline (l-Iva) conversely adopt the expected right-handed (P) helicity.…”

“…The three compounds 5 a, b, and d showed bands with characteristics of 3 10 helices with maxima at 208 nm accompanied by shoulders at 220 nm, [9] and comparison of the form of the CD spectra of the peptides 5 a, b bearing tertiary lamino acid residues with that of peptide 5 d bearing a quaternary l-amino acid residue suggested that the sense of helicity is opposite for the two classes. [23] Final confirmation that l-Val-capped Aib oligomers and l-aMv-capped Aib oligomers adopt opposite helical conformations was provided by 13 C NMR spectroscopy.…”

Induction of Unexpected Left‐Handed Helicity by an N‐Terminal L‐Amino Acid in an Otherwise Achiral Peptide Chain

“…[2] Collagen is an exception: its quaternary structure adopts right-handed helicity, but its individual peptide chains are long single-stranded left-handed helices, stabilized through intermolecular hydrogen bonds. For example, octamers of the achiral quaternary amino acid Aib (2aminoisobutyric acid) form 3 10 helices that interconvert rapidly in solution between the left-and right-handed helical conformations. [6] Peptides made entirely of achiral amino acids, even though they may form helical structures, can have no preference for left-or for right-handed helicity.…”

“…[6] Peptides made entirely of achiral amino acids, even though they may form helical structures, can have no preference for left-or for right-handed helicity. [10] Induction of helical preference [11] from the terminus of an otherwise achiral chain, mediated by stabilization of one of the two helical conformations, has been reported in several other classes of synthetic foldamers, [12] including dehydropeptides, [13] polyisocyanates, [14] polyureas, [15] and aromatic oligo-amides. [7] A single N-terminal l-amino acid is nonetheless sufficient to perturb measurably [8] the conformational ratio and can induce an absolute helical preference [9] in an entire chain of up to 20 achiral amino acids.…”