New self-assembled archetypes in crown ether substituted Δ ZPhe containing tripeptides

Article abstract of DOI:10.1007/s12039-019-1623-8

Abstract: We examine the effect of crown ether ring sizes on structure and properties of three terminally protected tripeptides containing substituted dehydrophenylalanine residues; Bz- Δ Phe (12-crown-4)-Phe-Phe-OMe, Bz- Δ Phe (15-crown-5)-Phe-Phe-OMe, Bz- Δ Phe (18-crown-6)-Phe-Phe-OMe. The resultant self-assembly of the peptides generates nano-vesicles, which further alter into the necklace type of structures that were characterized via their SEM, LRTEM, and AFM images. We also report the disruption of these vesicles in the presence of different metal ions. Graphical abstract:: Crown ether conjugated tripeptidesP-12C4 and P-15C5 showed a turn-on fluorescence in the presence of Hg ^{2 +} ions. While the peptides P-12C4 and P-15C5 self-assembled into nanovesicles, P-18C6 self-assembled into a necklace type of structures. Furthermore, incubation of P-12C4 and P-15C5 with Hg ^{2 +} and Na ⁺ ions resulted in the fusion of these well-defined nanovesicles.[Figure not available: see fulltext.].

Full text of DOI:10.1007/s12039-019-1623-8

J. Chem. Sci.
(2019) 131:47
© Indian Academy of Sciences
https://doi.org/10.1007/s12039-019-1623-8
REGULAR ARTICLE
Z
New self-assembled archetypes in crown ether substituted ꢀ Phe
containing tripeptides
∗
KALPANA TOMAR and GURUNATH RAMANATHAN
Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur, Uttar Pradesh 208016, India
E-mail: gurunath@iitk.ac.in
MS received 17 October 2018; revised 4 February 2019; accepted 18 March 2019
Abstract. We examine the effect of crown ether ring sizes on structure and properties of three
terminally protected tripeptides containing substituted dehydrophenylalanine residues; Bz-ꢀPhe(12-crown-
4)-Phe-Phe-OMe, Bz-ꢀPhe(15-crown-5)-Phe-Phe-OMe, Bz-ꢀPhe(18-crown-6)-Phe-Phe-OMe. The resultant
self-assembly of the peptides generates nano-vesicles, which further alter into the necklace type of structures
that were characterized via their SEM, LRTEM, and AFM images. We also report the disruption of these vesicles
in the presence of different metal ions.
Keywords. Crown ethers peptides; dehydrophenylalanine peptides; self-assembly; metal binding peptides.
1
. Introduction
Considering the potential advantages of the crown
ethers and Phe-Phe motif-based peptides, we have
synthesized the applications of the crown ether contain-
ing peptides. Here, crown ether containing tripeptides
were reported, namely P-12C4: Bz-ꢀPhe(12-crown-
Crown ethers are a class of macrocycles that possess
an uncanny ability to form metal complexes with the
alkali and alkaline earth metals, lanthanides, and tran-
sition metal ions. They have been widely applied in
the construction of molecular sensors as well as in
the design of ion-selective ligands using host-guest
chemistry. Interestingly, the modulation in the size of
crown ether rings enhances the sensing ability of these
molecules to specific metal ions. Crown ethers and their
derivatives are also known to form ordered structures.
For instance, crown ether substituted with Phthalocya-
nine can self-assemble into well-defined superhelical
4
)-Phe-Phe-OMe, P-15C5:Bz-ꢀPhe(15-crown-5)-Phe-
Phe-OMe, and P-18C6: Bz-ꢀPhe(18-crown-6)-Phe-
Phe-OMe (Figure 1). These tripeptides contained a
Z
Phe-Phe motif and ꢀ Phe residue with different crown
rings. Additionally, we also explored the metal sensing
abilityofthesepeptides. Interestingly, thesecrown-ether
containing tripeptides turned out to be promising lead
2
+
candidates for Hg ion sensing. The microscopic stud-
ies of the soft structures formed by these molecules
have demonstrated various nano-vesicular morpholo-
1
structures. Also, Voyer and coworkers have integrated
crown ethers into dihydroxyphenylalanine side chains to
produce substituted peptides. Phe-Phe based peptides
have also shown diverse self-assembled morphologies
2
+
gies which could rupture in the presence of Hg and
2
+
Na ions.
such as nanofiber, nanotubes, nanovesicles, micelles,
3
nanoribbons, etc. Recently, crown ether containing 2. Materials and methods
peptides have been explored in the biological applica-
tions. These applications include an ability to regulate 2.1 Material
enzyme activity, interact with or cleave DNA, and act
as antimicrobial agents. Several researchers have used
4
All amino acids barring ꢀPhe were of L-configuration. The
amino acids were procured from commercial sources. IR
spectra and CD spectra of peptides were recorded on Perkin
crown ether containing peptides in the preparation of
receptors, enzyme mimics, artificial ion channels, and
TM
Elmer spectrometer version 10.03.06 FT-IR and JASCO-
5
a, 4a, 5b, 4b, 1
dendrimers.
*
For correspondence
Electronic supplementary material: The online version of this article (https://doi.org/10.1007/s12039-019-1623-8) contains
supplementary material, which is available to authorized users.
0123456789().: V,-vol

47
Page 2 of 7
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(2019) 131:47
100
9
8
7
6
5
4
0
0
0
0
0
P-12C4
P-15C5
P-18C6
3
060
3
027
3
268
2
923
1
742
702
1
122
1662
1266
0
4
1514
000 3500 3000 2500 2000 1500 1000
-1
Wavenumber cm
Figure 1. Solid state FT-IR of peptides (recorded as KBr
pellet).
Scheme 1. Scheme for the synthesis of the tripeptides. (I)
Cs2CO3/CH3CN (II) CH3CO2Na/(CH3COO)2O, (III) ace-
tone/1 N NaOH, (IV) DCC/HOBt/DMF.
dichroism (CD) in solid and solution states. Due to the
presence of different functional groups such as CONH,
COOCH , aromatic rings, aliphatic groups (-CH ), etc.,
8
50 CD Spectropolarimeter respectively. Mass spectra were
3
2
1
recorded on Waters ESI-Q tof spectrometer. H NMR spec-
tra of peptides were recorded in JEOL ECS 400 MHz NMR
spectrometer using CDCl3 as a solvent. Absorption spectra
measurement was recorded on a Jasco V-550 UV-Visible
spectrophotometer, and emission spectra were recorded in
a Fluorolog 3.2.1 spectrofluorimeter. AFM samples were
imaged with XE70, Park system, South Korea, atomic force
microscope and FE-SEM images were recorded with an FEI
the solid-state FT-IR spectrum showed several vibra-
tional bands. The FT-IR bands spectrum for P-18C6 is
shown in Figure 1, and the assignments are listed in
Table 1.
−
1
All peptides show a single amide I peak at 1651 cm
−1
for P-12C4, 1662 cm for P-15C5 and P-18C6 indicat-
ing an α-helix turn type conformation. However, charac-
−
1
quanta 200 microscope. TEM samples imaged with FEI tecnai teristicabsorptionbandsintherangeof1610−1630cm
G2 12 twin TEM.
for the aggregated amyloid-like peptides is not observed
which suggests that these tripeptides do not aggregate
in the solid state.
2.2 Peptide synthesis strategy
CD spectrum revealed the most preferred conforma-
tion of these peptides in solution (Figure 2). While the
peptide P-12C4 shows sharp negative peak near 201 nm,
P-15C5 and P-18C6 show a sharp negative peak around
Peptides were synthesized by solution phase protocol6
(Scheme 1). The benzoyl protection was used at N-terminus
while C-terminus had methyl ester protection. Deprotection
of Boc (tert-butoxy carbonyl) was performed by 75% TFA
98 nm that is diagnostic for a random coil structure.7
1
(trifluoroacetic acid) in DCM (dichloromethane). Peptides
Persistence of some positive peaks indicates that pep-
tides also have a tendency to adopt other conformations
where the geometric arrangement of amide bonds are
different from those reported for a random coil structure.
The CD spectrum reflects the existence of various types
were coupled by using dicyclohexylcarbodiimide (DCC)/1-
hydroxy benzotriazole (HOBt). Intermediate peptides were
used directly without purification after ascertaining that there
was no racemization during the synthesis by high field NMR.
The final peptides were purified by column chromatography
using a methanol/chloroform gradient. Purified peptides were of molecular interactions present in this multi-sized self-
1
further characterized by ESI-MS and 400, 500 MHz H NMR assembled structure formed in the solution state.
in CDCl3.
3.2 Photophysical properties of peptides
3
. Results and Discussion
To investigate the effect of crown ether on fluorescence
properties of peptides, we used 50 μM solution of each
of these three peptides in methanol as a solvent. P-12C4
3.1 Conformational study of tripeptides
To obtain the secondary structure of these three peptides, displays an emission band at 403 nm on excitation at
we recorded Fourier transform infrared (FT-IR), circular 309 nm while P-15C5 and P-18C6 show emission band

J. Chem. Sci.
(2019) 131:47
Page 3 of 7
47
Table 1. Assignment of FT-IR bands present in the peptides.
IR frequency (cm 1
−
)
P-12C4
P-15C5
P-18C6
Modes of assignments
3295
3064
3028
2925
1743
1651
1506
1275
1140
702
3280
3062
3029
2926
1742
1662
1514
1266
1126
702
3268
3060
3027
2923
1742
1662
1514
1266
1122
702
Amide NH symmetric stretching
NH bending first overtone
Aromatic C-H stretching
-CH2 antisymmetric stretching
C=O stretching of the ester
Amide C=O stretching (amide I)
Amide II (NH bend in plane and CN stretch)
Amide III (NH bend in plane and CN stretch)
Ester C-O asymmetric stretch
Out of plane NH bending
1
.4
P-12C4
P-15C5
P-18C6
1
5
0
5
0
5
P-12C4_excitation
P-15C5_excitation
P-18C6_excitation
P-12C4_emission
P-15C5_emission
P-18C6_emission
406 nm
03 nm
1
1.2
4
1
.0
.8
3
09 nm
0
-
317 nm
-
-
-
-
10
15
20
25
0.6
0
.4
.2
0
2
00
210
220
230
240
250
0.0
Wavelength (nm)
200 250 300 350 400 450 500 550 600
Wavelength (nm)
Figure 2. Circular dichroic spectra of the peptides in
methanol (1 mg/mL in 0.1 mm cell).
Figure 3. Excitation and emission spectra of peptides
(50 μM) in methanol.
at 406 and 403 nm, respectively, on excitation at 317 nm
(
Figure 3). Fluorescence intensity of P-12C4 was lower
of these three peptides when cast on silicon wafers.
After a 12 h incubation, the peptides exhibit vesicular
structures which could be attributed to the hydrogen
bonding and π-π stacking. Moreover, a structural tran-
sition of self-assembled material is often commonly
in comparison to P-15C5 and P-18C6. We have also
measured the changes in fluorescence intensity of the
peptide in the presence of different metal perchlorate
salts. Significant changes in the fluorescence intensity
of P-12C4 and P-15C5 were found only in the presence
of Hg ion (Figures 4, 5). Peptide P-18C6 does not
show selectivity for any metal ion, but a does demon-
strate a subtle decrease in fluorescence intensity in the
presence of copper in comparison to other metal ions
8
observed in the literature. Both P-12C4 and P-15C5
2
+
self-assembled into vesicles with a smooth surface as
seen in atomic force microscopy (AFM), scanning elec-
tron microscopy (SEM) and low-resolution transmis-
sion electron microscopy (LRTEM) images (Figure 8).
Interestingly, the morphology of P-18C6 undergoes a
transformation from uniformly shaped nanovesicles of
P-12C4 and P-15C5 to a necklace-type of arrange-
ment with spherical beads which can be correlated
to the increase in crown ring cavity size (12-crown-
(
Figure 6). P-15C5, however, shows a marginally bet-
ter selectivity with mercury in comparison to P-12C4
Figure 7).
(
3
.3 Morphology and microscopic characterization
4
to 18-crown-6). Necklace type of structures, where
For the study of morphological architectures of pep- chains of beads are connected to form elongated soft-
tides, we have used 1 mM methanol solutions of each structures were observed in P-18C6 (Figure 8). For a

47
Page 4 of 7
J. Chem. Sci.
(2019) 131:47
1
000
2
+
(
A)
P12C4+Hg
P12C4
P-12C4
Cu
3
2
2
1
1
0
0
.0
(B)
.45
(C)
0
2
+
+
Ag
Ni
8
6
4
2
00
00
00
00
0
0.40
0.35
0.30
0.25
.5
.0
.5
.0
.5
.0
2+
2
+
+
Cd
Co
2
2
+
Fe
Ca
Hg
2
+
2
+
+
Na
0.20
0.15
0.10
2
00
250
300
350
400
350
400
450
500
550
600
0
2
4
6
8
10
2+
Wavelength (nm)
Mole fraction of Hg
Wavelength (nm)
Figure 4. (a) UV-vis spectra of P-12C4 (50 μM) with Hg2 ion. (b) Emission spectra with ten equivalents of perchlorate
+
2
+
salt of different metal ions, (c) Job’s plot of peptide P-12C4 showing 1:1 binding with Hg ions.
0
.40
P15C5
P15C5+Hg
(B)
P-15C5
(
A)
3
2
2
1
1
0
0
.0
.5
.0
.5
.0
.5
.0
+
(C)
2
+
2000
Na
Cu
2
+
0.35
0.30
0.25
0.20
0.15
0.10
+
Ag
2
+
Ni
1
500
000
2+
Cd2
+
Co
2
+
Fe
1
2+
Ca2
+
Hg
500
0
2
00
250
300
350
400
450
350
400
450
500
550
0
2
4
6
8
10
2
+
Wavelength (nm)
Wavelength (nm)
Mole fraction of Hg
Figure 5. (a) UV-vis spectra of P-15C5 (50 μM) Hg2 ion., (b) emission spectra with ten equivalents of perchlorate salt of
+
2
+
different metal ions, (c) Job’s plot of peptide P-15C5 showing 1:1 binding with Hg ions.
0
0
0
0
.50
.45
.40
.35
(
A)
P18C6
P18C6+Cu
7
6
5
4
3
00
00
00
00
00
(B)
P-18C6
(C)
2
1
1
0
0
.0
.5
.0
.5
.0
2
+
Na
Cu
Ag
+
2
+
+
2
+
+
Cd
Co
2
2
+
Ca
Hg
Fe
2
+
0.30
0.25
2
+
2
+
Ni
200
0
.20
.15
1
00
0
0
2
00
250
300
350
400
0
2
4
6
8
10
3
50
400
450
500
550
2+
Mole fraction of Cu
Wavelength (nm)
Wavelength (nm)
Figure 6. (a) UV-vis spectra of P-18C6 (50 μM) with Cu2 ion, (b) emission spectra with ten equivalents of perchlorate
+
2
+
salt of different metal ions, (c) Job’s plot of peptide P-18C6 showing 1:1 binding with Cu ions.
given building block of peptide molecules, its crown leads to interlinked necklace-like hollow spherical
ring cavity size and hydrophobicity on the exterior of particles.
the ring are responsible for this transformation. LRTEM
images corroborated well with the self-assembled struc-
tures observed in AFM and SEM images. Interlinked
solid spheres were observed for P-12C4 and P-15C5
while a better hydrogen bonding ability of P-18C6
3
.3a Peptide interaction with mercuric ions: Having
demonstrated the formation of vesicles and selectiv-
ity of peptides P-12C4 and P-15C5 towards Hg ion,
we aged the two solutions for 12 h and studied their
2
+

J. Chem. Sci.
(2019) 131:47
Page 5 of 7
47
fluorescence response and morphologies again in the
1
2
+
presence of Hg ions. There was no change in the
recorded fluorescence. Interaction of cations with the
peptides that trigger self-assembly is a well-studied phe-
0
.8
.6
.4
0
P1
P2
P3
0
9
nomenon. Moreover, mercury ions are also known to
0
.2
0
interact with the crown ether ring in the literature.10
Katerinopoulos and coworkers, recently designed a flu-
P3
1
2
3
4
5
6
P1
2+
7
8
orescent sensor for Hg with 7-amino-4 methylcouma-
1
0
11
rine andmonoaza-15-Crown-5. TheCaosgroupdevel-
oped a turn off sensor for mercuric ions bearing an
12
aza-15-crown-5 as a binding unit. The report of such
Figure 7. Comparison of emission of peptides with dif-
ferent metal ions in methanol at their λmax. [λmax for interactions prompted us to use mercury ion as an exter-
P-12C5 = 403 nm, for P-15C5 = 406 nm, P-18C6 = 403 nm].
nal stimuli to study peptides self-assembly. Peptides
(
P-12C4 and P-15C5) formed nanovesicles on incuba-
2
+
tion with the Hg ions in the 1:1 molar ratio. Peptides
2
+
were incubated with Hg for 12 h and displayed a
disintegration of these soft structures. SEM and TEM
micrographs revealed the disruption of the vesicular
structure (Figures 9, 10).
3
.3b Peptideswithsodiumions: Theaffinityofcrown
etherforalkaliandalkalineearthmetalsisawell-studied
phenomenon that catalyzes phase transfer reactions and
transports ions across lipophilic membranes. We rea-
soned that incubation of vesicles with alkali metal ions
like sodium ion might influence the self-assembly via
ion-dipole interactions with these cations. The known
proclivity of crown ethers to form complexes with
cations prompted us to use sodium ions as an external
Figure 8. Comparative self-assembled morpholo-
gies of crown ether substituted peptides as seen under
AFM, SEM, and LRTEM.
2
+
Figure 9. Microscopic images of peptide P-12C4+Hg complex in MeOH (a) SEM images.
b) LRTEM images (negative staining with 1% uranyl acetate). (c) EDX analysis.
(
2
+
Figure 10. Microscopic images of peptide P-15C5 + Hg complex in MeOH (a) SEM images.
b) TEM images (negative staining with 1% uranyl acetate). (c) EDX analysis.
(

47
Page 6 of 7
J. Chem. Sci.
(2019) 131:47
+
Figure 11. Microscopic images of peptide P-12C4+Na complex in MeOH (a) SEM images. (b) LRTEM
images (negative staining with 1% uranyl acetate). (c) EDX analysis.
+
Figure 12. Microscopic images of peptide 15C5 + Na complex in MeOH (a) LRTEM images (negative
staining with 1% uranyl acetate). (b) SEM images. (c) EDX analysis.
stimulus for altering peptide self-assembled structures. in the supplementary information available at www.ias.ac.in/
Interestingly, the vesicular structures ruptured after 12 h chemsci.
upon incubation of peptides (P-12C4, P-15C5) with
perchlorate salt of sodium even at ambient temperature
Acknowledgements
(
Figures 11,12).
KT thanks the Council of Scientific and industrial research
India) for a junior and senior research fellowship.
(
4
. Conclusions
Compliance with ethical standards
The synthesized tripeptides reported here adopt an α-
helical turn type conformation in the solid state and a
random coil (unordered pattern) in the solution. Interest-
Conflict of interest There are no conflicts to declare.
Z
ingly, these ꢀ Phe functionalized crown ether peptides
also show a potential to form complexes with metal ions.
The cation binding ability with varying crown ether ring
sizes could also be studied. Notably, peptides P-12C4
and P-15C5 have shown fluorescence turn-on sensing
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