Angewandte
Chemie
DOI: 10.1002/anie.201407329
Hybrid Peptides
Unprecedented Chain-Length-Dependent Conformational Conversion
Between 11/9 and 18/16 Helix in a/b-Hybrid Peptides**
Baptiste Legrand, Christophe Andrꢀ, Laure Moulat, Emmanuel Wenger, Claude Didierjean,
Emmanuel Aubert, Marie Christine Averlant-Petit, Jean Martinez, Monique Calmes,* and
Muriel Amblard*
Abstract: a,b-Hybrid oligomers of varying lengths with
alternating proteogenic a-amino acid and the rigid b2,3,3
boxylic acid residues (trans-ACPC residues) were able to
adopt both the 11 and 14/15 helix.[9,11] However, no evidence
of a helical fold was found for trans-2-aminocyclohexanecar-
boxylic acid-(trans-ACHC)-containing hybrid sequences.
Extended conformations were also preferred for oligomers
with alternating cis-ACHC and l-alanine,[17] whereas the
corresponding d-alanine-containing sequences that followed
the stereochemical patterning approach proposed by Fꢀlçp
and co-workers[14] adopted a distinct 11/9 helix.[16] Unlike
cycloalkyl-b2,3-amino acid-containing peptides, studies on a/b-
hybrid peptides involving hindered b-amino acid residues
such as gem-disubstituted b2,2- or b3,3-, acyclic disubstituted
b2,3-, or trisubstituted compounds, are rather limited. Early
work by Seebach et al.[2,18] assumed that such residues induce
steric hindrances that destabilize the secondary structures of
b peptides; as well, it was thought that the unfavorable
distribution of substituents in the amide plane might prevent
hydrogen bonding. However, a limited set of helical folds with
gem-dialkyl b-amino acids were recently obtained in combi-
nation with the a-aminoisobutyric (Aib) residue known to be
a strong helical inducer. Balaram et al.[19] demonstrated that
alternating Aib and the achiral cyclohexyl-b2,2-amino acid
residues resulted in an 11-helical fold in the tetra- and
pentapeptide. Another study involving Aib and an acyclic
trans-b2,3-amino acid, which normally promotes an extended
conformation in b peptides,[20] also described the formation of
an 11-helical structure in solution.[21]
-
trisubstituted bicyclic amino acid ABOC residues were studied
using both X-ray crystal and NMR solution structures. While
only an 11/9 helix was obtained in the solid state regardless of
the length of the oligomers, conformational polymorphism as
a chain-length-dependent phenomenon was observed in solu-
tion. Consistent with DFT calculations, we established that
short oligomers adopted an 11/9 helix, whereas an 18/16 helix
was favored for longer oligomers in solution. A rapid
interconversion between the 11/9 helix and the 18/16 helix
occurred for oligomers of intermediate length.
T
he development of heterogeneous backbones combining b-
amino acids with a-amino acids has significantly extended the
chemical and structural diversity of foldamers.[1–4] In recent
years, helical secondary structures of a,b-hybrid peptides
involving monosubstituted b2- or b3-amino acids[5–8] and
cycloalkyl-b2,3-amino acids[3,4,8–16] have been well described.
The ring-constrained b-amino acids constitute particularly
attractive building blocks to generate organized and func-
tionalized a,b-hybrid peptides. Within the family of foldamers
containing ring-constrained b-amino acids, unique conforma-
tions or conformational polymorphisms have been observed,
which were highly dependent on the structure and stereo-
chemistry of the individual building blocks. Indeed, short a,b-
hybrid oligomers containing trans-2-aminocyclopentanecar-
Herein, owing to the high propensity of the highly
constrained b2,3,3-trisubstituted bicyclic amino acid (S)-1-
aminobicyclo[2.2.2]octane-2-carboxylic acid (ABOC)[22] to
promote both a reverse turn into peptides[23] and stable
helix in homo- and mixed oligoureas,[24] we investigated its
incorporation into peptide sequences (Figure 1).
[*] Dr. B. Legrand,[+] Dr. C. Andrꢀ,[+] L. Moulat, Prof. J. Martinez,
Dr. M. Calmes, Dr. M. Amblard
IBMM, UMR 5247 CNRS, Universitꢀs Montpellier 1 et 2
15 avenue Charles Flahault, 34000 Montpellier (France)
E-mail: monique.calmes@univ-montp2.fr
ABOC combines the structural constraints of both
cyclohexyl- and gem-dialkyl-b-amino acids and thereby
exhibits limited range values of f, q, and y backbone
torsional angles. Indeed, it displays a high degree of con-
servation of the three angles with favorable gauche confor-
mations when incorporated into both the central position of
a reverse turn of a,b tripeptides, or when driving helical
folding of homo- or mixed oligoureas.[23,24] It is noteworthy
that the ABOC derivative has the ability to impose an
unexpected Ca–Cb synclinal conformation to the adjacent (S)-
b-amino acid derivative promoting the folding in mixed
oligoureas. Despite the strong ability of ABOC as helix
inducer in oligoureas, its incorporation in oligoamides to drive
helical systems has never been explored. Here, we inves-
tigated its impact to favor the folding among a/b-hybrid
Dr. M. C. Averlant-Petit
LCPM—UMR 7568 CNRS Universitꢀ de Lorraine
1 rue Grandville, 54001 Nancy Cedex 1 (France)
E. Wenger, Dr. C. Didierjean, Dr. E. Aubert
CRM2, UMR 7036 CNRS Universitꢀ de Lorraine
Boulevard des Aiguilletes
54506 Vandoeuvre-lꢁs-Nancy Cedex (France)
[+] These authors contributed equally to this work.
[**] We thank the CNRS, MESR, ANR (ANR-08-BLAN-0066-01), and the
LabEx CheMISyst for financial support, the SCBIM and Universitꢀ
de Lorraine for NMR and XRD facilities. GENCI-CINES is also
thanked for providing access to computing facilities.
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2014, 53, 13131 –13135
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
13131