A new peptide motif in the formation of supramolecular double helices

Article abstract of DOI:10.1039/c0cc04244g

The single crystal X-ray diffraction studies of a new tripeptide motif Boc-Tyr-Aib-Xaa-OMe (Xaa = Leu/Ile/Ala) reveal that the peptides adopt β-turn conformations which self-assemble to form a supramolecular double helical structure using various non-covalent interactions in the solid state and the peptides exhibit a type-III N₂ sorption isotherm.

Full text of DOI:10.1039/c0cc04244g

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A new peptide motif in the formation of supramolecular double helicesw
Poulami Jana, Sibaprasad Maity, Suman Kumar Maity and Debasish Haldar*
Received 6th October 2010, Accepted 7th December 2010
DOI: 10.1039/c0cc04244g
The single crystal X-ray diffraction studies of a new tripeptide
motif Boc-Tyr-Aib-Xaa-OMe (Xaa = Leu/Ile/Ala) reveal that
the peptides adopt b-turn conformations which self-assemble to
form a supramolecular double helical structure using various
non-covalent interactions in the solid state and the peptides
exhibit a type-III N2 sorption isotherm.
N-terminal L-tyrosine and central Aib (a-amino isobutyric
acid) residues. The new molecular scaffold Boc-Tyr-Aib-
Xaa-OMe (Xaa = Leu/Ile/Ala) adopts b-turn conformations
in the solid state and forms the supramolecular double helix in
higher order assembly, mainly directed by intermolecular
N–Hꢀ ꢀ ꢀO and O–Hꢀ ꢀ ꢀO hydrogen bonds.
A series of terminally protected tripeptides, Boc-Tyr-Aib-
Xaa-OMe, containing N-terminal L-tyrosine and central Aib
(a-amino isobutyric acid) residues (Xaa = Leu(1)/Ile(2)/
Ala(3)) have been synthesized by conventional solution-phase
methodology, purified, characterized, and studied (Fig. 1).
Colorless orthorhombic crystals of peptides 1, 2 and colorless
monoclinic crystals of peptide 3 suitable for X-ray diffraction
studies were obtained from their methanol–water solutions by
slow evaporation.z Peptides 1 and 2 crystallize with one
peptide molecule in the asymmetric unit (Fig. S1, ESIw).
However, peptide 3 crystallizes with two molecules of water
in the asymmetric unit (Fig. S1, ESIw). Interestingly, the
torsion angle around the conformationally constrained Aib
residue appears to play a critical role in dictating the overall
turn-like structural features.
Double helical structures are ubiquitous in nature and have
exclusive biological functions like information storage,
transcription and formation of ion channels.1 Hence there is
a general interest for designing biomimetic materials like
double helical structures of biopolymers by self-assembly of
the synthetic organic moiety.2 This interest stems from their
structural versatility, biocompatibility, robustness and
a
relative experimental simplicity. In recent years considerable
progress has been achieved in the design and characterization
of artificial oligomers that can wind around one another based
on the intrinsic nature of the motifs.3 Different kinds of duplex
structures have been developed, for example, on the basis of
metal–ligand interactions,4 H-bonds,5 ion pairing,6 aromatic–
aromatic interactions,7 hydrophobic interactions8 or p–p
interactions.9 Although plenty of supramolecular duplexes
held together by hydrogen bonds have been reported, most
of them are from large macromolecules and characterized as
ladder- or zipper-like linear structures.10 In this context, the
supramolecular double helix from self-assembling small
peptide building blocks by a combination of several non-
From the crystal structure of peptide 1, it is evident that
there is an intramolecular hydrogen bond between BOC CQO
and Leu NH resulting in a ten member hydrogen bonded
b-turn conformation in the solid state. The backbone torsion
angles of peptide 1 (Table 1) reveal that the turn is of distorted
type II b-turn. In comparison with peptide 1, peptide 2
contains one additional chiral centre (Ile residue). The
dihedral angles around the Ca of Aib of peptide 1 are in the
covalent interactions is highly interesting. Gorbitz has made
¨
a seminal contribution in structures of left-handed double
helices from hydrophobic dipeptides based exclusively on
a-amino acids (Val-Ala class structures).11 Banerjee and
coworkers have reported the formation of a double helix from
dipeptide containing N-terminal b-amino acids.12
As a part of our program aiming the investigation of helices
from synthetic oligomers,13 herein we present the formation of
supramolecular double helical structures in crystals from a
series of synthetic tripeptides (1–3), each containing
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, TGA data, Fig. S1–S13. CCDC
797096–797098. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c0cc04244g
Fig. 1 The schematic presentation of the reported peptide motifs 1–3.
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Table 1 The important backbone torsion angles of peptides 1–3
f1/1
c1/1
119.1
f2/1
62.4
c2/1
26.4
f3/1
c3/1
Peptide 1
Peptide 2
Peptide 3
ꢁ50.7
52.1
ꢁ59.0
ꢁ123.3
128.0
ꢁ151.8
ꢁ17.6
38.6
ꢁ178.6
ꢁ125.7 ꢁ64.2
ꢁ21.8
134.7 67.3
21.6
right handed a-helical region (f2 62.4; c2 26.41) and those for
peptide 2 are in the left handed a-helical region (f2 ꢁ64.2;
c2 ꢁ21.81). For peptide 2, the type II0 b-turn conformation has
been stabilized by a ten member intramolecular hydrogen
bond between BOC CQO and Ile NH. Though the backbone
torsion angles (Table 1) of peptide 3 are similar to that
of peptide 1 and are in the type II b-turn region of the
Ramachandran diagram, the peptide fails to form a ten
member intramolecular hydrogen bond. Moreover, peptide 3
exhibits a water mediated turn-structure in the solid state
(Fig. S1, ESIw).
Each peptide 1 and 2 molecules is then stacked one on top of
the other maintaining the proper registry to form an inter-
molecular hydrogen bonded helical strand along the crystallo-
graphic
c axis (Fig. 2). There are two intermolecular
hydrogen bonds (Tyr)N–Hꢀ ꢀ ꢀOQC(Leu/Ile) and side chain
phenolic–OH functionality of Tyr (O–Hꢀ ꢀ ꢀOQC) with Aib
CQO (ESIw, Tables S1 and S2) connecting individual peptide
molecules to form the supramolecular helical strand for
peptides 1 and 2 respectively.
Fig. 3 The double helical structures obtained from (a) peptide 1 and
(b) peptide 2.
The crystal structure further revealed that the two
individual helical strands are connected via non-covalent
interactions to form the double helical superstructure along
the axis parallel to the crystallographic c axis. Fig. 3 clearly
demonstrates that the individual b-turn subunits are stacked
by maintaining proper registry between the subunits, generating
a supramolecular individual helical strand which forms a
double helical structure upon further self-assembly. The
diameter of the supramolecular double helix is 36 A and rise
per turn of the helix is 77 A. The double helical structures
peptide molecules along the axis parallel to the crystallo-
graphic a axis. There are previous reports on the role of water
molecules in stabilizing supramolecular single stranded helical
structures in short peptides.14 The individual supramolecular
helical strand of peptide 3 further self-assembles to form a
double helical architecture along the crystallographic c axis
through non-covalent interactions (Fig. 4).
The TGA-DTA experiments show that the supramolecular
double helices have significant thermal stability (ESIw,
Fig. S2–S4). These tripeptides 1, 2 and 3 showed no
decomposition, phase transitions, or mass loss up to 196 1C
share some crystal packing similarities with the Gorbitz
¨
Val-Ala dipeptide.11
For peptide 3, the individual right handed helical strands are
formed by intermolecular hydrogen bonds between
(Tyr)N–Hꢀ ꢀ ꢀOQC(Tyr) and by intervening bridging water
molecules through intermolecular hydrogen bonding inter-
actions between Aib CQO and side chain phenolic–OH
functionality of Tyr (ESIw, Table S3) of properly arranged
Fig. 2 The formation of hydrogen bonded helical strand (a) and
(b) from peptide 1 and (c) and (d) from peptide 2.
Fig. 4 Formation of a water mediated double helix from peptide 3.
Chem. Commun., 2011, 47, 2092–2094 2093
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Data were processed using the Bruker SAINT package and the
structure solution and refinement procedures were performed using
SHELX97.16 The non-hydrogen atoms were refined with anisotropic
thermal parameters. The hydrogen atoms were included in geometric
positions and given thermal parameters equivalent to 1.2 times those
of the atom to which they were attached. The final R values were
for peptide 1: R1 0.0445 and wR2 0.1276 for 3641 data with
I > 2s(I). Peptide 2: R1 0.0409 and wR2 0.1482 for 4251 data
with I > 2s(I). Peptide 3: R1 0.0461 and wR2 0.1880 for 4397 data
with I > 2s(I). CCDC 797098, 797097 and 797096 for peptides 1, 2
and 3 respectively.
1 J. D. Watson and F. C. H. Crick, Nature, 1953, 171, 737.
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Fig. 5 N2 sorption isotherm of peptide 1 at 77 K (P0 = 1 atm). Black
square: sorption; red circle: desorption. Inset: mesoporous size
distribution of peptide 1 exhibits one peak at 6.50 nm.
(mp 164 1C), 187 1C (mp 137 1C) and 177 1C (mp 158 1C) for
peptides 1, 2, and 3, respectively.
In order to examine their double helix hollow, gas
absorption studies have been performed.15 The N2 sorption
studies with an evacuated sample of peptide 1 indicate that it
exhibits a type-III isotherm (Fig. 5). The pore size distribution
curve of tri-peptide showed one peak at 6.50 nm. The N2
uptake of peptide 1 crystal was found to be 18.31 cc gꢁ1
.
7 (a) V. Berl, I. Huc, R. Khoury, M. J. Krische and J.-M. Lehn,
Peptide 2 exhibits a similar N2 sorption isotherm but sorption
for peptide 3 is not satisfactory. Space between two helical
strands is ca. 3 nm for peptide 1 or 2 and ca. 1 nm for peptide 3
in crystal.
Nature, 2000, 407, 720; (b) C. Dolain, C. Zhan, J.-M. Le
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2008, 1968; (g) Q. Gan, F. Li, G. Li, B. Kauffmann, J. Xiang,
I. Huc and H. Jiang, Chem. Commun., 2010, 46, 297.
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K. Heremans and P. Herdewijn, Helv. Chim. Acta, 2001, 84, 2398.
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E. Yashima, J. Am. Chem. Soc., 2007, 129, 109; (c) H. Goto,
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In summary, we have shown that the self-assembly of a
series of tripeptides in a well-defined pattern may be directed
by similar intermolecular N–Hꢀ ꢀ ꢀO and O–Hꢀ ꢀ ꢀO hydrogen
bonds. In crystals the reported tripeptides adopt b-turn
conformations which further self-assemble to form a supra-
molecular double helical architecture. Boc-Tyr-Aib-Xaa-OMe
(Xaa = Leu/Ile/Ala) can be considered as a new molecular
scaffold for supramolecular double helix formation in the solid
state. Moreover, the peptides adsorb N2 in the double helix
hollow. The results presented here may foster new studies for
the design of useful nanoporous materials.
We acknowledge the DST, New Delhi, India, for financial
assistance Project No. (SR/FT/CS-041/2009). P. Jana,
S. Maity and S. K. Maity wishes to acknowledge the
C.S.I.R, New Delhi, India for research fellowship. We are
thankful to Dr Raju Mandal, Department of Inorganic
Chemistry, I.A.C.S., Jadavpur, Kolkata-700032, India for
his assistance in X-ray crystallography data refinement.
10 A. P. Bisson, F. J. Carver, D. S. Eggleston, R. C. Haltiwanger,
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State Mater. Sci., 2002, 6, 109–116.
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Notes and references
´
´
z Crystallographic data: peptide 1: C25H39N3O7, Mw = 493.59,
orthorhombic, space group P212121, a = 10.650(5), b = 14.144(5),
c = 18.399(8) A, U = 2771 A3, Z = 4, dm = 1.183 Mg mꢁ3. Peptide
2: C25H39N3O7, Mw = 493.59, orthorhombic, space group P212121,
a = 10.724(5), b = 14.233(5), c = 18.202(9) A, U = 2778 A3, Z = 4,
dm = 1.180 Mg mꢁ3. Peptide 3: C22H32N3O7ꢀ2H2O Mw = 486.54,
monoclinic, spacegroup C2, a = 27.262(12), b = 8.137(4), c =
13.415(6) A, U = 2675 A3, Z = 4, dm = 1.208 Mg mꢁ3. Intensity
data were collected with MoKa radiation at room temperature using a
Bruker APEX-2 CCD diffractometer. The crystal was positioned at
70 mm from the Image Plate. 100 frames were measured at 21 intervals
with a counting time of 5 min to give 5000 independent reflections.
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16 G. M. Sheldrick, SHELX 97, University of Gottingen, Germany,
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2094 Chem. Commun., 2011, 47, 2092–2094
This journal is The Royal Society of Chemistry 2011