A self-assembled tetrapeptide that acts as a “turn-on” fluorescent sensor for Hg2+ ion

Article abstract of DOI:10.1016/j.tetlet.2018.08.043

The tetrapeptide (Bz-ΔPhe(p-NPh₂)-L-DOPA(protected)-L-Phe-L-Phe-OMe was designed to incorporate seven phenyl rings so that it's conformation, self-assembly and application in Hg²⁺ ions sensing could be studied. Peptide molecules adopted an overlapping β-turn of type III/III conformation in crystals. The peptide showed a highly selective turn-on response towards mercuric ion over other metal ions with a 10-fold enhancement in fluorescence intensity. This intensity change coupled with the selectivity of the peptide towards mercury allowed us to demonstrate simple colorimetric dip sensing of Hg²⁺ ions. The technique provides a highly selective and effective way to detect Hg²⁺ ions. The peptide also self-assembled into nanospheres with diameter ranges from 100 to 500 nm. Mercuric ion coordination enabled these peptide nanospheres to aggregate into well-defined nanoparticles. The enhanced fluorescence upon Hg²⁺ addition demonstrates that peptide scaffolds can be exploited in the development of different selective sensors.

Full text of DOI:10.1016/j.tetlet.2018.08.043

Accepted Manuscript
A Self-assembled tetrapeptide that acts as a “turn-on” fluorescent sensor for
Hg2+ ion
Kalpana Tomar, Gagandeep Kaur, Sandeep Verma, Gurunath Ramanathan
PII:
S0040-4039(18)31044-X
https://doi.org/10.1016/j.tetlet.2018.08.043
TETL 50218
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
21 July 2018
21 August 2018
22 August 2018
Please cite this article as: Tomar, K., Kaur, G., Verma, S., Ramanathan, G., A Self-assembled tetrapeptide that acts
as a “turn-on” fluorescent sensor for Hg2+ ion, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.
2018.08.043
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A Self-assembled tetrapeptide that acts as a “turn-on” fluorescent sensor for Hg2+ ion
Kalpana Tomara, Gagandeep Kaura, Sandeep Verma,*a and Gurunath Ramanathan*a
700
P + Hg2+
600
500
400
300
200
P + Metals
100
250 nm
0
450
500
550
600
650
700
Wavelength (nm)
P + Hg2+
P + Hg2+
Self assembly
250 nm

1
Tetrahedron Letters
A Self-assembled tetrapeptide that acts as a “turn-on” fluorescent sensor for
Hg2+ ion
Kalpana Tomara,Gagandeep Kaura,Sandeep Verma,*a and Gurunath Ramanathan*a
a Department of chemistry, Indian Institute of Technology, Kanpur, India, 2018016
ARTICLE INFO
ABSTRACT
The tetrapeptide (Bz-∆Phe(p-NPh2)-L-DOPA(protected)-L-Phe-L-Phe-OMe was designed to
incorporate seven phenyl rings so that it’s conformation, self-assembly and application in Hg2+
ions sensing could be studied. Peptide molecules adopted an overlapping β-turn of type III/III
conformation in crystals. The peptide showed a highly selective turn-on response towards
mercuric ion over other metal ions with a 10-fold enhancement in fluorescence intensity. This
intensity change coupled with the selectivity of the peptide towards mercury allowed us to
demonstrate simple colorimetric dip sensing of Hg2+ ions. The technique provides a highly
selective and effective way to detect Hg2+ ions. The peptide also self-assembled into
nanospheres with diameter ranges from 100-500 nm. Mercuric ion coordination enabled these
peptide nanospheres to aggregate into well-defined nanoparticles. The enhanced fluorescence
upon Hg2+ addition demonstrates that peptide scaffolds can be exploited in the development of
different selective sensors.
Article history:
Received
Received in revised form
Accepted
Available online
Keywords:
Dehydrophenylalanine
Phenylalanine
Overlapping beta-turns
Mercury sensing
Self-assembly
2009 Elsevier Ltd. All rights reserved.
Introduction
physicochemical properties.29,30 Consequently, external stimuli-
sensitive self-assembling properties of peptides and specific
Rapid industrialisation in several parts of our world has led to
contamination of fresh water with heavy metal ions.1 Among
these, mercury is a major pollutant with adverse effects on human
health and environment. Small amounts of mercury in the human
body can trigger long-term irreversible damage to vital organs
and tissues such as kidney, liver, brain, nervous system etc.
These mercuric ion exposures often induce cognitive and motion
disorders.2-4
metal-peptide interactions can be exploited to yield fruitful routes
towards a more efficient bio-inspired metal peptide framework
(MPF) 31,32
Herein, we report a tetrapeptide that has been designed with a
protected L-DOPA, two phenylalanine and a benzyl protected
dehydrophenylalanine analogue (Scheme 1). From x-ray
crystallography, the peptide shows an overlapping β-turn
structure of a Type III/III conformation. This peptide further self-
assembled into nanospheres. We describe the application of this
peptide as a ratiometric “turn-on” fluorescence for Hg2+ ions in
acetonitrile solvent.
Spin-orbital couplings, energy transfer mechanisms or electron
transfer mechanisms typically result in fluorescence quenching in
the presence of many heavy metal ions (Cu2+, Hg2+, Pb2+).5,6
Thus, the detection of Hg2+ ions through fluorescence
enhancement is relatively scarce.7-11 Several peptide-based
chemosensors for heavy metal ions are reported in the
literature.12,7,13-15 and these chemosensors have their advantages.
Peptides can be easily synthesized to incorporate different
fluorophores. Besides, a high affinity and specificity can be
optimized by modulating the peptide backbone.16,17 Peptides can
be made water soluble. Peptides are biocompatible and also
We have crystallized the N-benzoyl protected peptide from
dichloromethane (DCM) solution through slow evaporation. The
structure was determined by X-ray diffraction. All the
crystallographic parameters are given in Table ST1. The peptide
adopted 310-helical conformation with an average value of all Φ,
Ψ as -60 and -30 respectively except Φ of the first residue and
Ψ of the last L-Phe residue. Torsion angles are listed in table
ST2. In the asymmetric unit, one molecule of the tetrapeptide
crystallized with two molecules of DCM. Crystal data revealed
that the tetrapeptide adopted an incipient 310-helical structure.
The overlapping β-turn of type III/III were stabilized through
intra and intermolecular N-H…O-C bond. The first turn involved
C21-O1...H4A-N4 hydrogen bond whereas other one involved
C21-O1... H5A-N5 hydrogen bond (Fig. 1). Table ST3 reports all
inter and intramolecular H-bonding found in the peptide crystal.
biodegradable. These features make peptides comparatively less
18-21
toxic in comparison to other chemical sensors.
Moreover,
peptides form variously ordered nanostructures22 that have been
exploited in various applications ranging from tissue
engineering,16 catalysis,17 drug delivery etc.23-26 Hydrogen
bonding, hydrophobic interactions and other weak interactions
are some of the major factors that regulate the self-assembly of
peptides.27,28 These soft molecular self-assembly also responds to
external stimuli like temperature, pH, light, electric field,
chemicals, ionic strength etc. The responses of soft structures to
stimuli often leads to
a predictable alteration in their

2
Tetrahedron Letters
ions such as Na+, Ca2+, K+, Zn2+, Ag+, Mn2+, Fe2+, Cd2+, Mn2+ in
a
b
acetonitrile solvent (Fig. 2). The emission spectra of ligand have
a weak emission band with maxima positioned around 525 nm
when excited at 370 nm (Fig. 2a). The fluorophore in the peptide
is
a
dehydrophenylalanine residue that combines an
intramolecular push-pull electronic effect and a conjugative
effect that results in a long wavelength excitation and a long
wavelength emission of the peptide. The alkali and other metal
ions exhibited no change relative to the emission spectra of the
peptide. While Hg2+ shows enhancement in fluorescence intensity
of peptide. However, upon addition of Hg2+, the fluorescence
emission band at 525 nm become blue shifted to 500 nm causing
a color emission changes from light yellowish to cyan under UV
light (Fig. 2b inset). Interestingly the colour change is not
observed with other metal ions which manifest its selectivity as
colorimetric sensor towards Hg2+ ions (Fig. S5). We investigated
binding stoichiometry of peptide with the Hg2+ ion. Job’s plot
analysis from fluorescence data in acetonitrile at excitation
wavelength 370 nm suggested a 1:1 stoichiometry of peptide
with Hg2+ ion (Fig. S4b). As per the formation of a complex with
1:1 ratio, we carried out fluorescence titration experiment in
CH3CN (Fig. 2c). A 50μM solution of the peptide was titrated
with different aliquots of the Hg2+ solution. However, on titration
of the peptide with Hg2+ (up to 10 equiv.), the fluorescence
intensity of peptide enhanced gradually (Fig. 2c). From the plot
Fig. 1 (a) Molecular structure of peptide. (b) Crystal structure of
peptide showing intramolecular hydrogen bonding. Only those
hydrogens which are involved in H-bonding are shown for clarity.
Along the c axis, the molecules pack in a head to the tail manner
that runs in antiparallel fashion (Fig. S2). Conventional CO...HN
Hydrogen bond [N2H2A…O5 = 2.69Å] links two molecules to
give a chain like structure as depicted in Figure S2. The stacking
of the molecules in the crystal is eclipsed along a axis (Fig. S1).
In addition to the conventional CO...HN hydrogen bonds, the
molecules exhibit other types of intermolecular interactions.
Intermolecular hydrogen bonding exists between the carbonyl
group of amide bond and C-H of an aromatic ring [C39-
O5…H23-C23 = 2.45Å and C48-O6…H32-C32 = 2.48Å] (Fig.
S3) One intermolecular CO…HC (CHO) bonding exist between
a carbonyl group of an amide bond and the CβH of L-dopa
involving C48-O6…H32B-C32 (2.30 Å). (Fig. S3). The closest
contact of one CH2Cl2 molecule to the peptide is to O2…H60-
C60 with a distance of 2.34 Å while second CH group has an
O4…H60A-C60 contact of 2.581 Å. It is noteworthy that
Intramolecular average distances of CO…HN bonding are larger
than intermolecular CO…HN hydrogen bonding (Table ST3).
I/I0 against [Hg2+]/uM, the value of K extracted from slope was
33,34
1.7X104 M-1. (Fig. 2d)
These binding constant quantitatively
suggest that peptide has a more potent binding affinity towards
Hg2+ in CH3CN. Based on fluorescence titration data, the
detection limit for Hg2+ detection was calculated to be 10 µM by
plotting the emission intensity at 500 nm against the
concentration of Hg2+ ions (Fig. 2c inset). The versatility of
sensing in the different solvent was checked by sensing in
different solvents which shows that all solvent is showing the
similar sensing except DCM (Fig. S6).
We report the differential optical response of tetrapeptide
towards Hg2+. The fluorometric behaviour of the peptide was
investigated in the presence of perchlorate salt of several metal
700
600
500
400
300
200
100
0
Peptide_excitation
Peptide_emission
b
a
1.2
1.0
0.8
0.6
0.4
0.2
0.0
We also investigated secondary structure of peptide and peptide
with mercury by CD spectroscopy. CD spectra of the peptide
indicate a turn type of structure with bands at 204 nm.35 On
addition of one equivalent of Hg2+ ion, a general shifting of the
band to 208nm is observed (Fig. S9) which further indicates that
there is no significant effect of Hg2+ ions on peptide turn type of
structure.
370 nm
525 nm
(A)
(B)
Peptide with Hg2+ ion
Peptide with other
metal ions
450
500
550
600
650
700
350 400 450 500 550 600 650 700
Wavelength (nm)
Wavelength (nm)
1.6
c 600
400
y = 0.01766x+ 1.03244
R2 = 0.99279
350
d
UV and fluorescence measurements for compound (4) and (6)
were recorded to determine if the binding site of Hg2+ ion
required the overlapping III/III beta-turn. UV and fluorescence
spectra were recorded for comp (4) in acetonitrile [at λex =
367nm, λem = 546nm] which shows no enhancement in
fluorescence intensity in the presence of Hg2+ ion (Fig. S7a, b).
Similar results were obtained for comp (6) [λex = 365nm and
λem = 507nm] (Fig. S8a, b). The emission results of these two
compounds in the presence of Hg2+ ions suggested that mercuric
ion specific binding requires the overlapping beta-turn scaffold.
The two tetrapeptides with dehydrophenylalanine analogue and
Aib residue have recently been reported from our group having
overlapping β-turns showing Hg2+ ion sensing in CH3OH
solvent.36
300
500
100 µM
1.5
1.4
1.3
1.2
1.1
250
200
150
400
300
200
100
0
1 µM
100
0
20
40
60
80
100
[Hg2+]/uM
450
500
550
600
650
5
10
15
20
25
30
[Hg2+]/uM
Wavelength (nm)
Fig. 2 (a) Excitation and emission spectra of the peptide (50 µM)).
(b)Emission spectra of the peptide (50 µM) in the presence of 10
equiv. of metal ions in acetonitrile (λex = 370 nm). Inset: the light
yellow colour of peptide with Hg2+ ion (A) turns cyan under UV
light (B). (c) Fluorescence titration spectra (λex = 370 nm) of the
peptide (50μM) in CH3CN upon increasing concentration of Hg2+.
Inset: fluorescent intensity at 500nm against the concentration of the
Hg2+ ion. (d) The stern-Volmer plot for a peptide with the Hg2+ ion.

3
Peptide (1 mM, CH3CN) was studied for its self-assembly
behaviour using various microscopic techniques as shown in
Figure 4. The peptide monomers self-assembled into highly
mono-dispersed spherical nanoparticles with a smooth surface as
observed in AFM images with an approximate diameter ranging
from 100-500 nm (Fig. 3, Fig. S10). Further, these spherical
particles were subjected to scanning electron microscopy (SEM)
(Figure 3b,c) and transmission electron microscopy (TEM)
studies (Fig. 3d,e). TEM studies revealed that the nanospheres
consisted of a hollow inner core (Fig. 3d,e) with diameter ranges
of 100-500 nm as shown in DLS spectrum (Fig. 3f). The
interactions observed in crystal structure for the formation of
these spherical structures were hydrophobic interactions and
hydrogen bonding within peptide molecules and with solvent
molecules.37-40
a
b
1 µm
1 µm
1
µm
c
d
d
d
e
e
a
b b
100 nm
250 nm
e
f
g
c
1 μm
1 μm
100 nm
c
d
images (Fig. 4a). The SEM images revealed the well-defined
fusion of spherical nanoparticles of peptides due to metal ion
Fig. 4 Microscopic images of peptide(9) (1mM, CH3CN) + Hg2+
(1mM, CH3CN) complex in CH3CN solvent with 1:1 ratio. (a) AFM
image. (b,c) SEM images. (d-e) TEM images. (f) EDX analysis (Si
and Au has been removed) (g) DLS spectrum.
1 µm
250 nm
f 90
e
75
60
45
30
15
0
interactions (Fig. 4b,c). Transmission electron microscopy
images exhibited the accumulation of Hg2+ ions into hollow
nanospheres of the peptide (Fig. 4d,e).
The fluorescence enhancement of peptide in the presence of
Hg2+ may be due to aggregation of the peptide by complexation
with mercury.41-44 Dynamic light scattering revealed that the
peptide did not aggregate (Fig. 3) by itself and showed negligible
fluorescent emission. Upon addition of mercury, the average
particle size increased (Fig. 4g) due to aggregation with an
enhancement of fluorescence intensity (Fig 2b). This
aggregation-induced emission (AIE) effect was further confirmed
by a microscopic study of the peptide in the presence and absence
of Hg2+ ions (Fig. 3,4).
100 nm
-100
0
100 200 300 400 500 600 700
Diameter (nm)
Fig. 3 Self-assembled structure of peptide (1mM, CH3CN). (a,) AFM
micrograph. (b,c) SEM images. (d,e) TEM images. (f) DLS spectrum
is showing size distribution of peptide.
Peptide with metal binding sites is interesting biomaterials for
MOF formation. Many reports of the metal-peptide framework
are reported in the literature. In recent literature, Jose et al.
reported a tripeptide based metal-organic framework for the
enantioselective separation of methamphetamine and ephedrine.31
However, in case of the peptide, the samples for metalation were
prepared with the perchlorate salt of Hg2+ in CH3CN (1:1 eq).
The microscopic studies revealed the fusion of the spherical
structures as shown by AFM, SEM and TEM images (Fig. 4).
The presence of Hg2+ ions was further established with energy
dispersive x-ray spectroscopy (EDX) analysis (Fig. 4f). The
peptide solution (1 mM) was incubated for 12 h to enable self-
assembly and then mixed with Hg2+ ions (1:1 eq). The fused
spherical particles were confirmed by atomic force microscopy
In conclusion, our reported self-assembling fluorescent
synthetic tetrapeptide with an overlapping turn of Type III/III
leading to an incipient 310 –helix is a viable probe for sensing of
Hg2+. The fluorescence intensity enhancement is a result of
peptide aggregation in the presence of mercuric ions. We believe
that improvement in the sensitivity of the peptide and
engineering its solubility in water can make this molecule a
promising tool for sensing mercury. Microscopic characterization
revealed a spherical morphology. However, detailed microscopic
studies reveal that interaction of the peptide with mercury ions
result in fusion of nanospheres of different sizes.
Acknowledgement

4
Tetrahedron Letters
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KT thanks the council of scientific and industrial research
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5
Highlights





We have synthesized dehydrophenylalanine
containing tetrapeptide.
Peptide folded as an overlapping beta-turn of
type III/III conformation.
The Peptide has been shown as a fluorometric
sensor for Hg2+ metal ion.
Peptide
self-assembled
into
spherical
nanoparticles.
Addition of Hg2+ in peptide solution results in
fusion of nanospheres.

6
Tetrahedron Letters