The herringbone helix: A noncanonical folding in aromatic-aliphatic peptides

Article abstract of DOI:10.1021/ja074285s

Hybrid oligomeric sequences derived from both aliphatic and aromatic units are shown to adopt a folded conformation with an unprecedented architecture. Specifically, a δ-amino acid bearing an aliphatic amine-6-aminomethyl-2-pyridinecarboxylic (P)-was designed and synthesized as a flexible analogue of 6-amino-2-quinolinecarboxylic acid (Q). Oligomers P_n (n = 2, 4, 8) were first synthesized but show no sign of folding in solution in organic solvents, unlike the Q_n oligomers from which they are derived, which adopt particularly stable helical conformations. Hybrid oligomers (PQ)_n (n = 1, 2, 4) were also prepared and were shown to adopt a novel folded conformation in the solid state where PQ units arrange into two stacks at a 90° angle from each other. Comprehensive NMR studies demonstrate that in solution this peculiar organization coexists with a helical conformation resembling that of Q_n oligomers. Copyright

Full text of DOI:10.1021/ja074285s

Published on Web 08/25/2007
The Herringbone Helix: A Noncanonical Folding in Aromatic-Aliphatic
Peptides
Nicolas Delsuc,† Fre´de´ric Godde,† Brice Kauffmann,† Jean-Michel Le´ger,‡ and Ivan Huc*,†
UniVersite´ Bordeaux 1-ENITAB-CNRS UMR 5248, Institut Europe´en de Chimie et Biologie, 2 rue Robert Escarpit,
33607 Pessac, France, and Laboratoire de Pharmacochimie, UniVersite´ Victor Segalen Bordeaux 2,
146 rue Le´o Saignat, 33076 Bordeaux, France
Received June 13, 2007; Revised Manuscript Received August 7, 2007; E-mail: i.huc@iecb.u-bordeaux.fr
Synthetic oligomers and polymers having folded conformations
in solutionsfoldamerssconstitute a chemically very diverse en-
semble.1 In contrast, the folding patterns themselves show less
diversity: most belong to the canonical folds found in biopolymerss
helices, turns, linear strandssand other folding modes as knots,2
“tail biters”,3 or pillars4 are rare. A reason for this may be that
canonical folds predominate in sequences based on the repeat of a
single folding codon and in sequences based on closely related
codons, as in R/â/γ-peptide hybrids5 or in aromatic peptide hybrids.6
Indeed, a majority of the reports of unconventional folds to date
concern the less explored oligomers that include folding codons of
different nature as, in particular, combinations of aliphatic and
aromatic backbone moieties.2-4,7 Consistent with this trend, we
herein describe the unprecedented folding mode of aromatic-
aliphatic δ-peptides.
Oligoamides of 8-amino-2-quinoline carboxylic acid (Q in
Figure 1) adopt exceptionally robust helically folded conformations
in solution8 and represent versatile building blocks to elaborate large
folded architectures.9 Robustness, however, is not always a desirable
Figure 1. Top: structures of monomers P and Q; (a) the backbone common
feature for biological applications and often causes synthetic
difficulties due to the resulting steric hindrance.10 We thus sought
for solutions to introduce flexibility within Qn oligomers, taking a
path opposite to that followed by many peptide chemists who
introduce rigidity into otherwise flexible backbones.11 Monomer P
(Figure 1) was designed as a structural analogue of Q that may
impart flexibility because of its reduced surface for intramolecular
π-π stacking and because its aliphatic methylene unit interrupts
π-conjugation and introduces an additional rotatable bond.
Molecular modeling studies were carried out to assess the
compatibility of P with folded helices of Q oligomers. As shown
in Figure 1b,c, energy minima are found for helical conformations
of P16 and (PQ)8 resembling Q16 helices.8,9 The two methylenic
protons which protrude on either side of the pyridine planes
apparently do not perturb intramolecular π-stacking, giving rise to
a helical pitch of 3.5 Å in all cases. The reduced bending angle at
the sp3 carbon negligibly alters curvature (2.5 units/turn).
to the two structures is emphasized by bold lines. Bottom: side view and
top view of energy minimized conformations (MacroModel v8.6; force field
MM3) of P16 (b) and (PQ)8 (c) as canonical helices and (PQ)8 (d) as a
noncanonical “herringbone” helix. Amide and quinoline moieties are shown
in gray; 6-aminomethyl units are shown in red. Isobutyl side chains have
been omitted for clarity.
Table 1. Chemical Shift Valuesa of Terminal Methylenic Ester
Protons
n
1
2
4
b
O2N-Q2n-OCH3
Boc-P2n-OCH3
4.23
4.01
4.11
3.46
3.94
3.62
3.01
3.91
3.57
Boc-(PQ)n-OCH3
a In CDCl3 at 25 °C. b The nitro group replaces the terminal NH unit.
of their conformation. This behavior reveals that P does impart
considerable conformational flexibility, and that the energy mini-
mum found in modeling studies (Figure 1b) is probably a shallow
minimum.
Encouraged by these findings, we prepared monomer P from
dimethyl 2,6-pyridinedicarboxylate (Figure 1) and undertook the
synthesis and conformational studies of P2n and (PQ)n oligomers
with n ) 1, 2, 4 (see Supporting Information). The 1H NMR spectra
of P2n oligomers in CDCl3, toluene-d8, or DMSO-d6 much contrast
with those of Q2n and readily suggest that no folding occurs for
this series in nonprotic solvents, even at low temperature. Specif-
ically, protons at equivalent positions of each unit give signals at
comparable chemical shifts regardless of the unit position in the
sequence and regardless of chain length (Table 1).12 Upon drying,
P2n oligomers form waxy solids, precluding crystallographic analysis
We expected that alternating Q with P monomers would restore
some rigidity and promote folding. Indeed, NMR spectra of (PQ)n
oligomers show sequence and chain length dependence of chemical
shifts (Table 1). A solid-state structure of (PQ)4 revealed a folded
architecture, but not the canonical helix (Figure 1c) expected by
analogy between P and Q. Instead, an unprecedented13 conformer
was observed in which PQ pairs form planes orthogonal to the
contiguous PQ pairs in the sequence. The 90° kink occurs where
the π-conjugated backbone is interrupted by the aliphatic methylenic
unit; it reflects the poor tendency of the 6-amidomethylpyridine to
form an intramolecularly hydrogen-bonded ring (Figure 2b). A
surprising feature is that this arrangement allows for a large overlap
and thus extensive π-π interactions between PQ pairs in position
† Universite´ Bordeaux 1-ENITAB-CNRS UMR 5248.
‡ Universite´ Victor Segalen Bordeaux.
9
11348
J. AM. CHEM. SOC. 2007, 129, 11348-11349
10.1021/ja074285s CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
together with the slight broadening of the spectra at lower
temperature suggest that the two types of folds coexist in solution.
Other folding modes cannot be strictly excluded. Fast equilibrium
on the NMR time scale is confirmed by the absence of diaste-
reotopic motifs in main chain and side chain methylenic signals
despite the chiral nature of the conformers. It might be speculated
that a subtle balance of P and Q monomers would favor one or the
other fold, or even allow for alternate patterns.
These results support the view that aliphatic-aromatic hybrid
oligomers often adopt unconventional conformations. Though
aliphatic moieties are reduced to methylene bridges in P2n and (PQ)n,
their effect on folding is dramatic. Such hybrids are likely to be
the object of increased scrutiny in the coming years.
Acknowledgment. This work was supported by an ANR grant
(project no. NT05-3_44880) and the Ministry of research.
Supporting Information Available: Synthetic procedures, char-
acterization of new compounds, spectroscopic data, and complete ref
6a. This material is available free of charge via the Internet at http://
pubs.acs.org.
References
Figure 2. (a) Stick and CPK representations of the crystal structure of
Boc(PQ)4OMe. Isobutyl chains and included solvent molecules have been
omitted for clarity. (b) Simplified schematic representation of a right-handed
herringbone helix showing two color-coded stacks of π-conjugated groups;
each group consists of a PQ dyad orthogonal to the previous and following
dyads in the sequence. Changes in the tilt angle of the strand with respect
to the axis are not depicted in this scheme (see Figure 1d). (c) Alternate
conformers resulting from 180° flips of the terminal PQ dyads. The structure
in (a) corresponds to form II.
(1) (a) Foldamers: Structure, Properties and Applications; Hecht, S. M., Huc,
I., Eds.; Wiley-VCH: Weinheim, Germany, 2007. (b) Goodman, C. M.;
Choi, S.; Shandler, S.; DeGrado, W. F. Nat. Chem. Biol. 2007, 3, 252-
262.
(2) (a) Bru¨ggemann, J.; Bitter, S.; Mu¨ller, S.; Mu¨ller, W. M.; Mu¨ller, U.;
Maier, N. M.; Lindner, W.; Vo¨gtle, F. Angew. Chem., Int. Ed. 2007, 46,
254-259. (b) Feigel, M.; Ladberg, R.; Engels, S.; Herbst-Hirmer, R.;
Fro¨hlich, R. Angew. Chem., Int. Ed. 2006, 45, 5698-5702.
(3) Hunter, C. A.; Spitaleri, A.; Tomas, S. Chem. Commun. 2005, 3691-
3693.
(4) (a) Gabriel, G. J.; Sorey, S.; Iverson, B. L. J. Am. Chem. Soc. 2005, 127,
2637-2640. (b) Ghosh, S.; Ramakrishnan, S. Angew. Chem., Int. Ed. 2004,
43, 3264-3268. (c) Zhang, W.; Horoszewski, D.; Decatur, J.; Nuckolls,
C. J. Am. Chem. Soc. 2003, 125, 4870-4873.
(5) (a) Hayen, A.; Schmitt, M. A.; Ngassa, F. N.; Thomasson, K. A.; Gellman,
S. H. Angew. Chem., Int. Ed. 2004, 43, 505-510. (b) De Pol, S.; Zorn,
C.; Klein, C. D.; Zerbe, O.; Reiser, O. Angew. Chem., Int. Ed. 2004, 43,
511-514. (c) Baldauf, C.; Gunther, R.; Hofmann, H.-J. J. Org. Chem.
2006, 71, 1200-1208. (d) Schmitt, M. A.; Choi, S. H.; Guzei, I. A.;
Gellman, S. H. J. Am. Chem. Soc. 2006, 128, 4538-4539. (e) Sharma,
G. V. M.; Jadhav, V. B.; Ramakrishna, K. V. S.; Jayaprakash, P.;
Narsimulu, K.; Subash, V.; Kunwar, A. C. J. Am. Chem. Soc. 2006, 128,
14657-14668. (f) Ananda, K.; Vasudev, P. G.; Sengupta, A.; Raja, K.
M. P.; Shamala, N.; Balaram, P. J. Am. Chem. Soc. 2005, 127, 16668-
16674.
(6) (a) Gong, B.; et al. Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 11583-11588.
(b) Garric, J.; Le´ger, J.-M.; Huc, I. Angew. Chem., Int. Ed. 2005, 44,
1954-1958.
(7) (a) Raynal, N.; Averlant-Petit, M.-C.; Berge´, G.; Didierjean, C.; Marraud,
M.; Duru, D.; Martinez, J.; Amblard, M. Tetrahedron Lett. 2007, 48,
1787-1790. (b) Baruah, P. K.; Sreedevi, N. K.; Gonnade, R.; Ravin-
dranathan, S.; Damodaran, K; Hofmann; H.-J.; Sanjayan, G. J. J. Org.
Chem. 2007, 72, 636-639.
(8) (a) Jiang, H.; Le´ger, J.-M.; Huc, I. J. Am. Chem. Soc. 2003, 125, 3448-
3449. (b) Jiang, H.; Le´ger, J.-M.; Dolain, C.; Guionneau, P.; Huc, I.
Tetrahedron 2003, 59, 8365-8374. (c) Dolain, C.; Gre´lard, A.; Laguerre,
M.; Jiang, H.; Maurizot, V.; Huc, I. Chem.sEur. J. 2005, 11, 6135-
6144.
(9) (a) Maurizot, V.; Dolain, C.; Leydet, Y.; Le´ger, J.-M.; Guionneau, P.;
Huc, I. J. Am. Chem. Soc. 2004, 126, 10049-10052. (b) Dolain, C.; Le´ger,
J.-M.; Delsuc, N.; Gornitzka, H.; Huc, I. Proc. Natl. Acad. Sci. U.S.A.
2005, 102, 16146-16151. (c) Delsuc, N.; Le´ger, J.-M.; Massip, S.; Huc.
I. Angew. Chem., Int. Ed. 2007, 46, 214-217.
(10) Zhang, A.; Ferguson, J. S.; Yamato, K.; Zheng, C.; Gong, B. Org. Lett.
2006, 8, 5117-5120.
Figure 3. NOE correlations compatible with a herringbone helix (solid
lines), with a canonical helix (dotted lines), and with both (dashed line).
i and i+2. The resulting structure is helical in that it possesses a
twist sense but does not fit the canonical definition of a helix: the
tilt angle with respect to the helix axis is not constant but changes
sign four times per turn at each pyridine methylene and carbonyl
group (Figure 1d). Thus, the overall aspect of the fold is that of
two stacks of aromatic rings perpendicular to each other, resembling
a herringbone motif. Modeling studies confirm that (i) such a pattern
can be propagated over long sequences (Figure 1d); (ii) terminal
PQ pairs can be flipped by 180° without disrupting the rest of the
structure (Figure 2c); and (iii) this 180° rotation cannot be
accommodated at PQ pairs within the sequence without perturbing
π-π stacking due to internal sterics.
NMR structure studies were carried out to assess whether the
structure found in the solid state also prevails in solution. Spectra
are slightly broad at 25 °C, broaden further upon cooling, and
sharpen upon heating. A full assignment of the spectra was possible
in toluene-d8 at 75 °C based on HMBC and HSQC experiments as
described previously.8c NOESY experiments allowed us to identify
seven strong NOE correlations between protons remote in the
sequence (Figure 3). Four of them are indeed compatible with the
herringbone fold observed in the solid state, or to alternate
herringbone helices where terminal PQ units may be flipped by
180°, but other correlations are incompatible and, on the contrary,
match with a canonical helical fold (Figure 1c). These results
(11) For examples, see: (a) Chapman, R. N.; Dimartino, G.; Arora, P. S. J.
Am. Chem. Soc. 2004, 126, 12252-12253. (b) Nicoll, A. J.; Miller, D. J.;
Fu¨tterer, K.; Ravelli, R.; Allemann, R. K. J. Am. Chem. Soc. 2006, 128,
9187-8193. (c) Schafmeister, C. E.; Po, J.; Verdine, G. L. J. Am. Chem.
Soc. 2000, 122, 5891-5892.
(12) Stone, M. T.; Heemstra, J. M.; Moore, J. S. Acc. Chem. Res. 2006, 39,
11-20.
(13) Ring closure may impose related conformations in macrocycles: Toyota,
S.; Goichi, M.; Kotani, M. Angew. Chem., Int. Ed. 2004, 43, 2248-2251.
JA074285S
9
J. AM. CHEM. SOC. VOL. 129, NO. 37, 2007 11349