Supramolecular double helix from capped γ-peptide

Article abstract of DOI:10.1039/c1cc15570a

The single crystal X-ray diffraction study of capped γ-peptide reveal that the peptide adopts helical conformation which self-assemble to form a supramolecular parallel double helical structure using intermolecular hydrogen bonding as well as π-π stacking

Full text of DOI:10.1039/c1cc15570a

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Supramolecular double helix from capped c-peptidew
Suman Kumar Maity, Sibaprasad Maity, Poulami Jana and Debasish Haldar*
Received 8th September 2011, Accepted 17th November 2011
DOI: 10.1039/c1cc15570a
The single crystal X-ray diffraction study of capped c-peptide
reveal that the peptide adopts helical conformation which self-
assemble to form a supramolecular parallel double helical
structure using intermolecular hydrogen bonding as well as
p–p stacking interactions in the solid state.
obtained from linear oligoamide strands have been used as a
template for cross-olefin metathesis.10 Huc and coworkers
have designed helical molecular tapes of aromatic oligo-
amides11 to slowly wind around rod-like guests and then to
rapidly slide along them, where the winding process requires
helix unfolding and refolding, as well as a strict match between
helix length and anchor points on the rods.12
Nature achieves a wide range of double helical structures and
functions like information storage, transcription and for-
mation of ion channels from relatively small number of
building block such as four nucleobases and twenty amino
acids.1 Chemical synthesis of biopolymer mimics has advan-
tage to play with the wide range of building blocks.2 Over the
past few years, considerable progress has been achieved in the
design, synthesis and characterization of artificial oligomers
that can wind around one another based on the intrinsic
nature of the foldamers.3 Plenty of intertwined supramolecular
duplexes from the abiotic backbone that are assembled by
H-bond donor/acceptor sites are known, although most of the
reported double helices are DNA analogues and derivatives
containing regular base-pairs.4 A small number of studies are
also representative of non-DNA-based hydrogen bonded
double helices.5 Yashima and colleagues have designed and
synthesized an amidinium–carboxylate salt bridge m-terphenyl
derivative by direct double helix-to-double helix transforma-
tions using the Pt(II) acetylide complexes as the surrogate
linkers and removing the Pt(II) linkers by treatment with
iodine, where the supramolecular double helical structure
can be stabilized by intermolecular salt bridge formation.6
Aromatic interactions based on alternating stacking of elec-
tron rich 1,5-dialkoxy-naphthalene and electron poor 1,4,5,8-
naphthalene-tetracarboxylic diimide systems to stabilize the
double helical structure were introduced by Gabriel and
Iverson.7 The principle of p–p and CH–p interactions also
exists between oligoresorcinols that self-assemble into double
helices in water.8 Synthetic double-stranded molecules that are
held together by noncovalent interactions also have potential
application.9 For example, hydrogen-bonded duplexes
We have reported that the interstrand side chains–side
chains interactions can significantly increase the hybridization
constant of the pyridine derived oligoamide foldamer.13,14
Moreover, the hybridization of pyridine carboxyamide oligo-
mers enhanced dramatically with increasing oligoamide length
and terminal Boc protection.15 Intriguing the information
from previous reports we have designed foldamers 1 and 2
incorporating m-amino benzoic acid and capped with Boc and
N,N0-dicyclohexylurea. In the solid state the peptide 1 forms
an antiparallel hydrogen bonded dimer and peptide
2
dimerizes as a parallel double helix through intermolecular
hydrogen bonding and p–p stacking interactions.
The g-peptides 1 and 2 containing m-amino benzoic acid
and capped with Boc and N,N0-dicyclohexylurea have been
synthesized by conventional solution-phase methodology,
purified, characterized, and studied (Fig. 1). The assumption
was that m-aminobenzoic acid should impart a helical propensity
in the g-peptides16 and N,N0-dicyclohexylurea should enhance
intermolecular hydrogen bonding interaction as seen in the other
urea derivatives.
In order to understand conformational features of the
capped g-peptides in solution, NMR studies were performed.
The concentration dependent 1H NMR study in CDCl3
exhibits significant downfield shift of the amide protons with
increasing concentration (Fig. S1, ESIw), which suggest that
Department of Chemical Sciences, Indian Institute of Science
Education and Research Kolkata, Mohanpur, West Bengal 741252,
India. E-mail: deba_h76@yahoo.com, deba_h76@iiserkol.ac.in;
Fax: +91 3325873020; Tel: +91 3325873119
w Electronic supplementary information (ESI) available: Synthesis
and characterization of peptides, 1H NMR, 13C NMR, solid state
FTIR spectra, Table S1, Fig. S1–S19. CCDC 832274 and 832275. For
crystallographic data in CIF or other electronic format see DOI:
10.1039/c1cc15570a
Fig. 1 The schematic presentation of the reported g-peptides 1 and 2.
Chem. Commun., 2012, 48, 711–713 711
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Fig. 3 Crystal structure of intermolecular hydrogen bonded (dotted
lines) antiparallel dimers obtained from peptide 1. Cyclohexyl groups
here appear as orange spheres and t-butyl groups as violet spheres.
Non-active H atoms have been omitted for clarity. Some torsion
angles are included.
Fig. 2 Plot of solvent dependence of NH chemical shifts of peptides 1
and 2 at varying concentrations of (CD3)2SO in CDCl3 solutions.
the NH protons are hydrogen bonded. The upfield shifts of
amide protons upon heating of peptide 2 in CDCl3 (Fig. S2,
ESIw) suggest that some hydrogen bonds are broken upon
increasing temperature. To determine whether the hydrogen
bonds are intramolecular or intermolecular, solvent titration
experiments have been performed. The effects of adding a
hydrogen bond accepting solvent like (CD3)2SO to CDCl3
solutions of peptides 1 and 2 are represented in Fig. 2. Generally,
addition of small amounts of (CD3)2SO in CDCl3 brings about
monotonic downfield shifts of exposed NH groups in peptides,
leaving solvent-shielded NH groups largely unaffected.17 Fig. 2
shows that all NHs are solvent exposed as it is evident from their
significant chemical shift upon the addition of (CD3)2SO in
CDCl3 solutions. For both the peptides, urea NH exhibits
minimum chemical shift (Dd 0.20 for peptide 1 and 0.36 for
peptide 2) even at higher percentages of (CD3)2SO. However, the
Boc NH shows maximum chemical shift (Dd 0.58 for peptide 1
and 0.76 for peptide 2). Table S1 (ESIw) illustrates Dd values of
all NHs for peptides 1 and 2. The Maba(2)NH of peptide 2 is
also solvent exposed (Dd 0.70). This demonstrates that peptides 1
and 2 cannot form any intramolecular hydrogen bonded structure
in solution.17 Moreover, the NOESY spectrum at 50 mM
concentration exhibits NOE intensities which are responsible
for intermolecular interaction between aromatic protons
(Fig. S3, ESIw). Other solution phase techniques such as circular
dichroism, UV-vis and fluorescence spectroscopy were per-
formed. CD spectrums of peptides 1 and 2 in CHCl3 (Fig. S4,
ESIw) have positive bands at 212 nm and 226 nm and a negative
band at 220 nm.
CQO and m-aminobenzoic acid N–H leading to anti-parallel
dimers (Fig. 3). These dimers are in turn connected to neigh-
boring dimers through the N1–H1ꢀ ꢀ ꢀO7 (2.14 A, 2.96(6) A,
1601) and N4–H4ꢀ ꢀ ꢀO3 (2.12 A, 2.97(7) A, 1751) hydrogen
bonds into two-dimensional layers (Fig. S6, ESIw), viewed here
along the a axis.
However, one molecule of peptide 2 crystallizes with one
molecule of chloroform in the asymmetric unit (Fig. S7, ESIw).
The torsion angle around the m-aminobenzoic acid residues
(f1 = ꢁ31.3(3)1, c1 = ꢁ28.0(2)1, f2 = ꢁ154.7(16)1, c2 =
142.4(17)1) appears to play a critical role in dictating the
overall structural features. For peptide 2, in higher order
assembly, a parallel double helix has been observed. Contacts
between the main chains of the two strands consist of edge-
to-face aromatic stacking and four interstrand N–Hꢀ ꢀ ꢀO
hydrogen bonds. The duplex is stabilized through intermolecular
hydrogen bonding interactions (N1–H1ꢀꢀꢀO3, 2.12(2) A, 2.92(2) A,
153(2)1, 1 ꢁ x, y, 1/2 ꢁ z and N3–H3ꢀꢀꢀO2, 2.35(2) A, 3.18(2) A,
163(2)1, 1 ꢁ x, y, 1/2 ꢁ z) between two strands (Fig. 4).
Thus the urea and Boc capping have significant contribution
in the duplex stabilization. Unlike other oligoamide double
helical foldamers, there is only a p–p interaction between the
The solid state conformations of peptides 1 and 2 have been
studied by X-ray crystallography. Colorless triclinic crystals of
peptide 1 and colorless orthorhombic crystals of peptide 2
suitable for X-ray diffraction studies were obtained from their
chloroform–hexane solutions by slow evaporation.z In the
solid state, peptide 1 crystallizes with two molecules in the
asymmetric unit (Fig. S5a, ESIw). This is a centrosymmetric
structure. The two molecules in the asymmetric unit are
actually very similar except the orientations of the cyclohexyl
groups attached to N2/N5, and when these are removed, a
least squares fit is close to perfect (Fig. S5b, ESIw). From the
crystal structure of peptide 1, it is evident that there are two
intermolecular hydrogen bonds (N3–H3ꢀꢀꢀO4, 2.12 A, 2.97(7) A,
1721 and N6–H6ꢀ ꢀ ꢀO8, 2.05 A, 2.89(7) A, 1671) between urea
Fig. 4 The inter strand hydrogen bonded double helix of peptide 2.
Hydrogen bonds are shown as dotted lines. Cyclohexyl groups here
appear as orange spheres and t-butyl groups as violet spheres. Non-
active H atoms have been omitted for clarity.
c
712 Chem. Commun., 2012, 48, 711–713
This journal is The Royal Society of Chemistry 2012

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and wR2 = 0.1700 for 2678 data with I 4 2s(I). Peptide 2:
C32H42N4O5, Mw = 562.70, orthorhombic, space group Pbcn, a =
19.0609(13), b = 19.6825(14), c = 18.9838(13) A, V = 7122.1(9) A3,
Z = 8, dc = 1.050 Mg mꢁ3, T = 100 K, R1 = 0.0540 and wR2
=
0.1398 for 5064 data with I 4 2s(I). Intensity data were collected with
MoKa radiation for peptide 1 at 296 K and MoKa radiation for
peptide 2 at 100 K using a Bruker APEX-2 CCD diffractometer. Data
were processed using the Bruker SAINT package and the structure
solution and refinement procedures were performed using
SHELX97.19 For peptide 1 non-hydrogen atoms were refined with
anisotropic thermal parameters. For peptide 2, the non-hydrogen
atoms were refined with isotropic thermal parameters due to closely
spaced Cl atoms in the solvent molecule. The PLATON/SQUEEZE
program20 was used on the raw data to generate a new dataset that
removed the scattering contribution of disordered solvent molecule.
Fig. 5 (a) Fluorescence spectra and (b) UV-vis spectra of peptide 2
with different concentrations of sulfamethoxazole added.
1 (a) M. M. Cox and D. L. Nelson, Principles of biochemistry, W.H.
Freeman and Company, New York, 2008; (b) A. Bruce, Molecular
Biology of the Cell, Garland Science, New York, 2008.
strands. Maba(1) of strand A stacks over Maba(2) of strand B
(shortest C–C distance is 3.54 A) and reciprocally.18 The two
molecules related by proper two-fold rotation symmetry generate
a dimer. There is no solvent molecule inside the double helix
channel. In higher order packing each double helical structure
forms an intermolecular hydrogen bond (N4–H4ꢀꢀꢀO5, 2.01(2) A,
2.83(2) A, 161(2)1, ꢁ1/2 + x, 1/2 + y, 1/2 ꢁ z) with four other
double helices (Fig. S8, ESIw) where CHCl3 molecules are
simply filling voids in the crystal lattice.
2 (a) S. Hecht and I. Huc, Foldamers: structure, properties and
applications, Wiley-Vch verlag Gmbh, Weinheim, 2007;
(b) D. Seebach and G. Gardiner, Acc. Chem. Res., 2008,
41, 1366; (c) B. Gong, Acc. Chem. Res., 2008, 41, 1376;
(d) Z.-T. Li, J.-L. Hou and C. Li, Acc. Chem. Res., 2008,
41, 1343; (e) C. M. Goodman, S. Choi, S. Shandler and
W. F. DeGrado, Nat. Chem. Biol., 2007, 3, 252; (f) Z.-T. Li,
J.-L. Hou, C. Li and H.-P. Yi, Chem.–Asian J., 2006, 1, 766;
(g) I. Huc, Eur. J. Org. Chem., 2004, 17.
3 (a) D. J. Hill, M. J. Mio, R. B. Prince, T. S. Hughes and
J. S. Moore, Chem. Rev., 2001, 101, 3893; (b) R. P. Cheng,
S. H. Gellman and W. F. DeGrado, Chem. Rev., 2001, 101, 3219.
4 (a) B. Petersson, B. B. Nielsen, H. Rasmussen, I. K. Larsen,
M. Gajhede, P. E. Nielsen and J. S. Kastrup, J. Am. Chem. Soc.,
2005, 127, 1424; (b) K. Augustyns, F. Vandendriessche, A. Van
Aerschot, R. Busson, C. Urbankel and P. Herdewijn, Nucleic Acids
Moreover, the NMR chemical shift of NH protons with
addition of sulfamethoxazole exhibits that peptide 2 interacts with
a potent bacteriostatic antibiotic sulfamethoxazole (Fig. S9, ESIw).
For further investigation, UV-vis and fluorescence experiments
were performed as it is a very sensitive technique to study the
changes in microenvironment (Fig. 5). Initially the fluorescence
intensity at 375 nm increases with increasing drug concentration.
But, after a certain point, a red shift at 395 nm has been observed,
which indicates a strong interaction between drug molecules and
peptide 2. The fluorescence of sulfamethoxazole interferes with
that of peptide 2. X-Ray quality crystal of the complex is not
obtained.
Res., 1992, 20, 4711; (c) M. Tarkoy and C. Leumann, Angew.
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´
In summary, we have shown that the ability of helical
foldamers to form double helices is not restricted to the aromatic
oligoamides but also applies to urea and Boc capped conforma-
tionally constrained peptides. The parallel double helix is stabi-
lized by multiple intermolecular hydrogen bonds as well as p–p
stacking interaction. The capped g-peptides can be considered as
a new molecular scaffold for supramolecular double helix formation
in the solid state. The results presented here may foster new studies
for the design of capped g-peptides leading to cross-hybridization
and sequence-selective recognition.
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I. Huc, Chem.–Asian J., 2010, 5, 1364.
We acknowledge the DST, India, for financial assistance
(Project No. SR/FT/CS-041/2009). S. K. Maity, S. Maity and
P. Jana acknowledge the C.S.I.R, India, for research fellowship.
We are thankful to Dr Raju Mandal, I. A. C. S., Jadavpur,
Kolkata-700032, India, for his assistance in X-ray crystallography
data refinement. We thank the reviewers.
´
ger and
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Notes and references
19 G. M. Sheldrick, SHELX 97, University of Gottingen, Germany,
¨
z Crystallographic data: Peptide 1: C25H37N3O4, Mw = 443.58,
triclinic, space group P1, a = 12.4834(8), b = 13.8403(9), c =
14.9746(10) A, a = 91.506(4)1, b = 95.452(4)1, g = 90.632(4)1, V =
2574.4(3) A3, Z = 4, dc = 1.145 Mg mꢁ3, T = 296 K, R1 = 0.0541
1997.
20 P. v. d. Sluis and A. L. Spek, Acta Crystallogr., Sect. A: Found.
Crystallogr., 1990, 46, 194.
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Chem. Commun., 2012, 48, 711–713 713