Nanofiber formation of amphiphilic cyclic tri-β-peptide

Article abstract of DOI:10.1002/psc.1206

A novel amphiphilic cyclic peptide composed of two β-glucosamino acids and one trans-2-aminocyclohexylcarboxylic acid was synthesized and investigated on assembly formation. The cyclic tri-β-peptide was self-assembled into rodlike crystals or nanofibers depending on preparative conditions. The rodlike crystals showed a layer spacing of 4.8 A along the long axis, and columnar spacings of 10.8 and 21.5 A by electron diffraction analysis along the short axis. The former confirms the columnar structure upon molecular stacking, and the latter indicates triple bundle formation of the columnar assemblies. Fourier transform infrared (FT-IR) measurement of the fibrous assembly showed formation of homogeneous hydrogen bonds among amide groups, also supporting the molecular stacking of cyclic β-peptides. Straight nanofibers with uniform diameter were also uniquely obtained. Copyright

Full text of DOI:10.1002/psc.1206

Research Article
Received: 24 July 2009
Revised: 21 November 2009
Accepted: 23 November 2009
Published online in Wiley Interscience:
(www.interscience.com) DOI 10.1002/psc.1206
Nanofiber formation of amphiphilic cyclic
tri-β-peptide
Yusuke Ishihara and Shunsaku Kimura∗
A novel amphiphilic cyclic peptide composed of two β-glucosamino acids and one trans-2-aminocyclohexylcarboxylic acid
was synthesized and investigated on assembly formation. The cyclic tri-β-peptide was self-assembled into rodlike crystals or
nanofibers depending on preparative conditions. The rodlike crystals showed a layer spacing of 4.8 Å along the long axis,
and columnar spacings of 10.8 and 21.5 Å by electron diffraction analysis along the short axis. The former confirms the
columnar structure upon molecular stacking, and the latter indicates triple bundle formation of the columnar assemblies.
Fourier transform infrared (FT-IR) measurement of the fibrous assembly showed formation of homogeneous hydrogen bonds
among amide groups, also supporting the molecular stacking of cyclic β-peptides. Straight nanofibers with uniform diameter
c
were also uniquely obtained. Copyright ꢀ 2010 European Peptide Society and John Wiley & Sons, Ltd.
Keywords: β-amino acid; cyclic peptide; self-assembly; nanofiber; amphiphilic peptide
Introduction
Here we have synthesized an amphiphilic CP2 to study the
PNT and the bundle formation. As shown in Figure 1(a), CP2
is composed of two hydrophilic GAs and one hydrophobic
ACHC. CP2 is expected to stack together to form PNT, and in
aqueous environment three PNTs should associate reasonably
well with the hydrophobic ACHC residue facing inward and the
two hydrophilic GA residues pointing outward (Figure 1(b–d)).
In our previous report, CP2 of ACHC produced a crystal of PNTs
aligned in a parallel manner. The parallel orientation is considered
to be due to the interdigitation of cyclohexyl side chains between
PNTs. If CP2 would hold this unique property of ACHC, three
PNTs in the bundle should possess an extremely large dipole.
The morphology and structure of molecular assemblies of CP2
are thus studied here mainly by transmission electron microscopy
(TEM) observations by changing the peptide concentrations.
Organic nanosize fibrous molecular assemblies have attracted
much attention with regard to functional materials in the fields of
materials science [1–4] and biomaterials [5–9], etc. Peptides have
been frequently used for the nanofiber preparations because
peptides tend to associate together via intermolecular hydrogen
bonds like β-sheet structure [10–19]. Size and surface properties
of the peptide assemblies are adjustable for various materials
by proper design of the primary structure. [20] Surface design
of peptide assemblies was also reported with peptide nanotubes
(PNTs), which are generally characterized by molecular stacking of
cyclic peptides of α- [21–25] and β-amino acids [26–28] via inter-
molecular hydrogen bonds with the formation of a well-defined
pore inside. The pore size is controllable precisely by changing
the number of constituent amino acids of the cyclic peptides.
Further, PNTs composed of β-amino acids are unique
in exhibiting a strong dipole moment along the nanotube
axis. We have prepared several cyclic β-peptides to inves-
tigate the nanotube formation and its functionalization. We
have chosen trans-2-aminocyclohexylcarboxylic (ACHC) acid and
β-glucosamino acid (GA) as components of cyclic β-peptides be-
cause the cyclic side chains promote molecular stacking to yield
long and stable nanotubes due to the planar geometry. However,
PNTs have a strong tendency to associate together to form thick
bundles,probablybecausethedipole–dipoleinteractionbetween
PNTs attracts them to take an antiparallel orientation, leading to
the formation of thick bundles [28–30]. Control of the PNT number
in the bundles to keep it small is therefore challenging.
Materials and Methods
Spectroscopic Measurements
NMR spectra were recorded with a Bruker DPX-400 spectrometer.
FAB mass spectra were obtained on a JEOL JMS HX-110A
spectrometer. FT-IR was performed with a Nicolet 6700 FT-IR
spectrometer.
Structure Calculation
Geometry optimization was carried out by the CAChe software
(Fujitu Co., Japan), the molecular Mechanics program 2 (MM2),
and the semi-empirical Austin Model (AM1) method in the MOPAC
2002 package.
One typical way to control the bundle size is to use the
leucine-zipper motif in addition to introduction of complementary
ionic groups to each helical chain as found in the coiled-coil
structure[31–33]. However, thesemoleculardesignswouldnotbe
applicable to PNTs, because they influence the molecular stacking
manner of cyclic peptides. The other way is to be endowed with
an amphiphilic property [20,34,35]. In the present study, we tried
to control the association number of PNTs in the bundle by using
an amphiphilic cyclic tri-β-peptide (CP2).
∗
Correspondence to: Shunsaku Kimura, Department of Material Chemistry,
Graduate School of Engineering, Kyoto University, Kyoto-Daigaku-Katsura,
Nishikyo-ku, Kyoto 615-8510, Japan. E-mail: shun@scl.kyoto-u.ac.jp
Department of Material Chemistry, Graduate School of Engineering, Kyoto
University, Kyoto-Daigaku-Katsura, Nishikyo-ku, Kyoto 615-8510, Japan
c
J. Pept. Sci. 2010; 16: 110–114
Copyright ꢀ 2010 European Peptide Society and John Wiley & Sons, Ltd.

STRAIGHT AND UNIFORM NANOFIBER FORMATION
Figure 1. (a) The cyclic tri-β-peptide CP2 is composed of two hydrophilic GAs and one hydrophobic ACHC. (b) Geometry-optimized structure of cyclic
tri-β-peptide, CP2. (c) (Top panel: top view, bottom panel: side view), schematic illustration of PNT from CP2. (d) Scheme of association of three CP2
molecules based on the amphiphilic structure. Hydrophobic cyclohexyl side chains are aligned in a straight form to make the surface hydrophobic. The
other surface is hydrophilic, thus leading to association of PNTs.
Optical Microscopy
Boc-((GA(OAc))2ACHC)-OCH2C6H5 (2)
The Boc group of compound 1 (669 mg, 0.77 mmol) was removed
with TFA and anisole. The obtained salt, Boc-GA(OAc)-OH (366 mg,
0.85 mmol), and HATU (349 mg, 0.92 mmol) were dissolved in DMF
and stirred at 0 ◦C for 10 min. DIEA (265 µl, 1.52 mmol) was added
to the mixture, and stirred at 0 ◦C for 3 h and at r.t. overnight. The
mixture was concentrated, diluted with CHCl3, and washed with
4% KHSO4 aq, 4% NaHCO3 aq, and brine. The organic layer was
driedoverMgSO4.Afterevaporationofthesolvent,theresiduewas
washedwithdiisopropyletherforthreetimestoprovide2(752 mg,
Optical microscopy was performed with an Olympus IX70. A
dispersion of crystals was placed between a slide glass and a cover
glass, and observed under cross-Nicol configuration. The sensitive
tint plate was set between the polarizers.
TEM and Electron Diffraction
The images and diffraction were taken with JEOL JEM-2000EXII
(JEOL, Japan) at an accelerating voltage of 100 kV. A drop of the
sample was dried on a carbon-coated Cu grid.
The electron diffraction diagrams were obtained in the
microdiffraction mode. The distance in the diffractions was
calibratedwiththe(111)diffractionringofevaporatedAuparticles.
1
0.636 mmol, 83%): Rf 0.80 (10 : 1 chloroform/methanol). H-NMR
(400 MHz, CDCl3): δ 7.31 (m, 5H, C6H5), 6.98 (1H, sugar amide NH),
6.73 (d, 1H, J = 8.9 Hz, cyclohexane amide NH) 5.10–4.97 (m, 4H,
H-3, 3ꢁ, 4, 4ꢁ), 4.71 (1H, urethane NH), 4.24 (td, 1H, J = 5.5, 12.0 Hz,
cyclohexane H-2), 4.15–3.97 (4H, H-6, 6ꢁ), 3.75–3.59 (m, 6H, 1, 1ꢁ,
2, 2ꢁ, 5, 5ꢁ), 2.31 (t, 1H, J = 10.52 Hz, cyclohexane H-1), 2.03 (18H, 6
acetyl), 1.26 (9H, Boc Me), 1.70–1.17 (cyclohexane 3–6); MS (FAB,
matrix: nitrobenzyl alcohol): m/z 964.5 (calcd. for C45H61N3O20
[(M+H)+], m/z 964.4).
Scanning Electron Microscope (SEM)
The image was taken with Keyence VE-8800 at an accelerating
voltage of 5 kV. A drop of the sample was dried on a Au-coated
glass.
Boc-((GA(OAc))2ACHC)-OH (3)
A solution of compound 2 (752 mg, 0.636 mmol) in CH2Cl2
(156.6 ml) was subjected to catalytic hydrogenation in the
presence of 20% palladium on activated carbon palladium black
(235 mg) for 26 h. The catalyst was removed through cellite and
the solvent was evaporated to yield the product 3 (508 mg,
Synthesis of Cyclic Peptide
Boc-(GA(OAc)-ACHC)-OCH2C6H5 (1)
1
0.576 mmol, 91%): Rf 0.53 (10 : 1 chloroform/methanol). H-NMR
p-TosOH H-ACHC-OBn [36] (470 mg, 1.16 mmol), Boc-GA(OAc)-OH
[37] (437 mg, 1.05 mmol), and HATU (526 mg, 1.39 mmol) were
dissolved in DMF (4 ml). DIEA (640 µl, 3.68 mmol) was added to
the mixture at 0 ◦C and stirred at 0 ◦C for 2 h and r.t. overnight.
The mixture was concentrated, diluted with CHCl3, and washed
successively with 4% KHSO4 aq., saturated NaHCO3 aq., and
brine. The organic layer was dried over MgSO4. The solution
was concentrated and purified by silica gel chromatography
(100 : 1 CHCl3/MeOH) to provide 1 (358 mg, 39%): Rf 0.51 (10 : 1
(400 MHz, CDCl3): δ 6.70 (1H, sugar amide NH), 6.63 (d, 1H,
J = 8.0 Hz, cyclohexane amide NH), 5.67 (t, 1H, J = 10.0, H-3ꢁ),
5.32–5.14 (t, 1H, J = 9.8 Hz, H-3), 5.05–4.96(3H, H-4, 4ꢁ, urethane
NH), 4.27–4.23, 4.06–3.97 (4H, H-6, 6ꢁ), 4.20–4.12 (3H, H-2, 2ꢁ,
cyclohexane 2), 3.76–3.60 (2H, H-5, 5ꢁ), 1.45 (9H, Boc), 2.01 (18H,
6 acetyl), 1.26–1.10 (8H, H-3, 4, 5, 6); MS (FAB, matrix: nitrobenzyl
alcohol): m/z 874.4 (calcd. for C38H55N3O20 [(M+H)+], m/z 874.4).
CP2(OAc) (4)
1
chloroform/methanol). H-NMR (400 MHz, CDCl3): δ 7.23 (m, 5H,
C6H5), 6.15 (d, 1H, J = 8.5 Hz, urethane NH), 5.14–5.07 (m, 1H,
H–3ꢁ), 5.06–5.01(d, 2H, J = 12.1 Hz, benzyl), 4.99(t, 1H, J = 9.5 Hz,
H-4ꢁ), 4.60 (s, 1H, amide), 4.21 (dd, 1H, J = 9.0, 12.6 Hz, H-6ꢁa),
4.02–3.91 (2H, H-2ꢁ, 6ꢁb), 3.69–3.59 (2H, H-1ꢁ, 2), 3.55–3.49 (m, 1H,
H-5ꢁ), 2.33 (td, 1H, J = 11.6, 4.0 Hz, H-1), 2.09–2.00 (9H, 3 acetyl),
1.70–1.17 (8H, H-3, 4, 5, 6); MS (FAB, matrix: nitrobenzyl alcohol):
m/z 649.3 (calcd. for C32H44N2O12 [(M+H)+], m/z 649.3).
The Boc group of compound 3 (37 mg, 0.042 mmol) was removed
with TFA and anisole. The obtained salt, HATU (159.6 mg,
0.42 mmol), and HOAt (84 mg, 0.63 mmol) were dissolved in
DMF (42 ml) and stirred at 0 ◦C for 10 min; then DIEA (134.4 µl,
0.756 mmol) in DMF (7.6 ml) was added dropwise, and the solution
was stirred at 0 ◦C for 3 h, and at r.t. for 28 h. After evaporation,
the residue was washed with methanol (several times) and hot
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J. Pept. Sci. 2010; 16: 110–114 Copyright ꢀ 2010 European Peptide Society and John Wiley & Sons, Ltd. www.interscience.com/journal/psc

ISHIHARA AND KIMURA
methanol (one time) to yield product 4 (31 mg, 95%): Rf 0.45 (10 : 1
chloroform/methanol). 1H-NMR (400 MHz, dimethylsulfoxide-d6):
δ 7.45 (d, 1H, J = 9.52, GAa amide NH), 7.17 (d, 1H, J = 8.00 Hz,
GAa amide NH), 7.08 (d, 1H, J = 9.04, ACHC amide NH), 5.18 (t,
1H, J = 9.24 Hz, GAb 3), 5.08 (t, 1H, J = 9.8 Hz, GAa 3), 4.86 (t, 1H,
J = 9.52, GAa 4), 4.80 (t, 1H, J = 9.52 Hz, GAb 4), 4.16–4.07 (5H,
GAa 6, GAb 6, GAa 2), 4.40–4.01 (3H, GAa 1, GAb 1,2), 3.96–3.91
(3H, ACHC 2, GAa 5, GAb 5), 2.02–1.89 (18H, 6 acetyl), 1.79–1.11
(8H, ACHC 3, 4, 5, 6); MS (FAB, matrix: nitrobenzyl alcohol): m/z
778.4 (calcd. for C33H45N3O17Na [(M+Na)+], m/z 778.3).
CP2
Compound 4 (21.4 mg, 28.3 µmol) was dissolved in DMSO (3.1 ml),
and 1N NaOH aq. (0.286 µl) was added to the solution. The mixture
was stirred at 60 ◦C for 12 h. The mixture was neutralized with
a 1 N HCl aq. The crude product was precipitated with acetone
and diethyl ether. The residue was washed with acetone and
water, and water was removed by freeze drying to yield the
product CP2 (10.5 mg, 74%): Rf 0.79 (Reversed-phase TLC, 50 : 5 : 1
methanol/formic acid/water). 1H-NMR (400 MHz, formic acid-d2):
δ 4.65(d, 1H, J = 6.00, GAab 1), 4.62 (d, 1H, J = 6.00, GAb 1),
4.50–4.45 (4H, GAab 2, 3), 4.16–3.83 (8H, GAab 4, 5, 6), 2.35 (td,
1H, J = 2.3, 10.1, ACHC NHCH), 1.96 (1H, ACHC COCH), 1.65–1.25
(8H, ACHC 3–6); MS (FAB, matrix: nitrobenzyl alcohol): m/z 526.2
(calcd. for C21H33N3O11Na [(M+Na)+], m/z 526.2).
Figure 2. Optical microscopic observation at a cross-Nicol configuration
of CP2 crystals. The double-headed allow shows the orientation of zꢁ-axis
of a sensitive tint plate. Bar = 10 µm.
Results and Discussion
Polarization Microscope Observation
CP2 is soluble in dimethylsulfoxide and formic acid, but pratically
insoluble in water, N,N-dimethylformamide, and chloroform.
The poor solubility is probably due to the facile formation of
intermolecular hydrogen bonds. Rodlike crystals of CP2 were
successfully obtained from a mixed solution of formic acid
and diisopropyl ether. The crystals exhibited a highly ordered
structure as shown by the polarization microscope observation
with a sensitive tint plate (Figure 2), where a yellow-orange color
(subtraction retardation) was observed in the case of parallel
orientation between the long axis of the rodlike crystal and the zꢁ-
axis of the tint plate, and a blue color (addition retardation) in the
case of their perpendicular orientation. The observation indicates
that the short axis of the crystal has a larger refractive index than
that of the long axis. In the previous reports of cyclo(ACHC)3 [36]
and cyclo(GA)3 [38], the refractive index along the long axis was
larger than that along the short axis due to the alignment of amide
bonds along the long axis. In the case of CP2, hydrogen bonds
between hydroxyl groups of neighboring PNTs may be formed
and make the refractive index larger along the short axis.
Figure 3. Electron diffraction pattern obtained with an incident electron
beam perpendicular to the long axis of the rod-shaped assembly of CP2.
Notably, alternative light and dark spots along the short axis
are observed in Figure 3, indicating the presence of spacing
distances of 10.8 and 21.5 Å. The former length corresponds
to the column diameter, which corresponds to the ring size
of the planar CP2 structure. The latter length may reflect the
triple bundle structure (Figure 1(d)), which was expected from
the design of the amphiphilic CP2 that should associate into a
trimer by facing the cyclohexyl units inward and exposing the
pyranose moieties outside. The planar structure composed of
three CP2 molecules should stack together via intermolecular
hydrogen bond formation to give the triple bundle structure. The
orientation of the columns in the bundle is either all parallel or two
parallel and one opposite. In the case of cyclo(ACHC)3, all parallel
orientation was found in the crystal due to interdigitation of the
cyclohexyl units. As diffraction spots appear at the intersections
between the central meridian axis and the first layer lines [29,30],
the columns should contain antiparallel alignment. The difference
between CP2 and cyclo(ACHC)3 is the multiple hydrogen-bond
formation among PNTs, which may weaken the interdigitation
effect of ACHC residues. However, details remain to be solved.
Electron Diffraction Analysis
The CP2 crystals of 1.5–2 µm diameter and 15–40 µm length were
subjected to the electron diffraction analysis. The electron beam
was irradiated at the thin section of the specimen to obtain the
diffraction pattern (Figure 3), which reveals a spacing of 4.8 Å
along the long axis [29,30,39]. This length fits into the molecular
thickness of the planar CP2 structure, and is consistent with the
formation of columnar structure by CP2 stacking similar to the
reports on other cyclic tri-β-peptides (Figure 1(c)) [29,30,36,38].
c
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STRAIGHT AND UNIFORM NANOFIBER FORMATION
IR Analysis
A solution of CP2 in formic acid and water (7/3 v/v) at 1.1 × 10−3
M was dried slowly on a CaF2 plate in air and then in vacuo. An FT-
IR spectrum of this white solid showed an amide I absorption
(mainly C O stretching mode) and an amide II absorption
(mainly N–H bending and C–N stretching modes) at 1665 and
1565 cm−1 respectively. A sharp N–H stretching peak appeared at
3277 cm−1,supportingthatCP2formsthecolumnarstructurewith
homogeneous intermolecular hydrogen bonds. We estimated a
stacking distance between CP2 molecules in the column from the
N–H stretching frequency. According to the Krimm’s analysis, the
distance between nitrogen and oxygen atoms via the hydrogen
bond is calculated to be ca 2.9 Å [36,39]. Further, the distance
between nitrogen and oxygen atoms in the amide along the
columnar axis is estimated to be 1.9 Å by geometry optimization.
The sum of the two distances is the same as the axial spacing
evaluated from the diffraction analysis of the CP2 crystal. CP2 thus
shows a high tendency to form the columnar structure.
Figure 4. TEM image of molecular assembly prepared from 1.1 × 10−5
solution of CP2 in formic acid and water (7/3 v/v). Bar = 50 nm.
M
Fibrous Molecular Assembly from Formic Acid and Water
CP2 is a planar cyclic peptide with amide bonds oriented
perpendicular to the ring to form PNT as shown in Figure 1(b) and
(c). These PNTs tend to associate together to yield thick bundles
despitethemoleculardesigntoinducethetriplebundleformation.
The facile association of PNTs may be due to the hydroxyl groups
exposed on the outside of the triple bundle, which can readily
make interbundle hydrogen bonds as adhesive forces. However,
we have examined the effect of the peptide concentration during
preparation of the crystalline molecular assemblies on molecular
assembly sizes.
When a solution of CP2 in formic acid and water (7/3 v/v) at a
concentrationof1.1×10−5 M wasdriedonacarbon-coatedcopper
TEM grid, a rod-shaped assembly of ca 5 nm diameter, which
corresponds to a nine-columnar (3× triple bundle) structure, was
foundasthedominantsizeeventhoughtherodsizesvariedwidely
(Figure 4). By increasing the peptide concentration to 1.1×10−4 M,
a uniform fibrous assembly of ca 15 nm in diameter and more than
3 µm in length was obtained (Figure 5). When the concentration
was raised up to 1.1 × 10−3 M, uniform and straight fibers of
ca 100 nm in diameter and more than 60 µm in length were
obtained (Figure 6). This observation contrasts those of winding
fibers formed with β-sheet peptides [16–19] or amphiphilic block
peptides [14,15,20,40]. The highly straight morphology of CP2
nanofibers might be due to the straight morphology of PNTs
and the tight association between neighboring PNTs by multiple
hydrogen-bond formation among hydroxyl groups.
Our initial purpose to obtain a thin bundle of PNTs is partially
attained by formation of a rod-shaped assembly of ca 5 nm
diameter, which should be composed of three of the initially
designed triple bundles. By increasing the peptide concentrations
in the assembly process, the number of triple bundles in the rod-
shaped assemblies became higher, thus thickening the nanofibers
to diameters of up to ca 100 nm. The reason for this thickening
may be the multiple hydrogen-bond formation between hydroxyl
groups on the PNT surfaces. We are looking for other functional
groups to decorate the PNT surface to avoid the thickening effects
and thus to attempt the preparation of PNT bundles with large
dipole moments [41].
Figure 5. TEM image of molecular assembly prepared from 1.1 × 10−4
solution of CP2 in formic acid and water (7/3 v/v). Bar = 300 nm.
M
Figure 6. SEM image of molecular assembly prepared from 1.1 × 10−3
solution of CP2. Bar = 5 µm.
M
Conclusion
A novel amphiphilic cyclic tri-β-peptide composed of two GAs
and one ACHC was synthesized. This cyclic peptide was self-
assembled into rodlike crystals or fibrous assemblies. TEM
observation, electron diffraction analysis, and FT-IR spectroscopy
indicated the PNT formation. The amphiphilic molecular structure
contributed to association of three molecules into a trimeric unit.
The molecular assemblies were stabilized by molecular stacking
through hydrogen bonds between amides of the cyclic peptides
c
J. Pept. Sci. 2010; 16: 110–114 Copyright ꢀ 2010 European Peptide Society and John Wiley & Sons, Ltd. www.interscience.com/journal/psc

ISHIHARA AND KIMURA
and interbundle hydrogen bonds through hydroxyl groups. By
using a high concentration in the preparation, nanofibers of a
highly straight form and composed of a higher number of triple
bundles were obtained.
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Acknowledgements
Authors thank Prof. J. Sugiyama and Dr. Y. Horikawa (Kyoto
University Research institution for Sustainable Humanosphere) for
their help in the TEM, SEM, and electron diffraction measurements.
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