Modulating the Phe-Phe dipeptide aggregation landscape via covalent attachment of an azobenzene photoswitch

Article abstract of DOI:10.1039/c7cc04106c

Synthetic control of peptide-based supramolecular assemblies can provide molecular cues to understand protein aggregation while also inspiring the development of novel chemical biology tools to deliver cargoes inside cells. Here we show that the trans-to-

Full text of DOI:10.1039/c7cc04106c

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Modulating Phe‐Phe dipeptide aggregation landscape by covalent
attachment of an Azobenzene photoswitch
Received 00th January 20xx,
Accepted 00th January 20xx
Melby Johny,a† Kanchustambham Vijayalakshmi,a Ankita Das,a Palas Roy,a Aseem Mishra,b* and
Jyotishman Dasguptaa*
DOI: 10.1039/x0xx00000x
www.rsc.org/
Synthetic control on peptide‐based supramolecular assemblies aggregates in solution, Li and co‐workers demonstrated light‐
can provide molecular cues to understand protein aggregation induced morphology change from branched chains to vesicular
while also inspiring development of novel chemical biology tools form by co‐assembling an azo‐photoswitch containing cationic
to deliver cargo inside cells. Here we show that trans‐to‐cis detergent tail with Phe‐Phe dipeptide.6 It was argued that such
photoisomerization of a pendant azo‐group covalently attached to dynamic control on self‐assembly originates from the strong
Phe‐Phe dipeptide can comprehensively ‘turn‐off’ its native influence of aromatic π‐stacking interaction.1b,4b,7 Additionally,
fibrillation propensity as well as provide an optical handle to molecular dynamics simulations show that inter‐peptide H‐
reversibly switch the aggregate morphology from fibril‐to‐vesicle.
bonding play crucial role in stabilizing the superstructures.3a
Recently photo‐induced morphological switching of Phe‐Phe
dipeptide was shown by covalent attachment of an Azo‐switch
incarcerated inside α‐cyclodextrin at the N‐terminus.8
However this work did not directly tinker with the underlying
molecular interactions that govern the aggregation of the core
Phe‐Phe motif.
Self‐assembly of phenylalanine‐phenylalanine (Phe‐Phe)
dipeptide has drawn significant attention due to its inherent
kinetic diversity of aggregation pathways while being derived
from the core aggregation motif of disease causing amyloid‐β
(Aβ) peptide.1 The high backbone flexibility of the basic Phe‐
Phe construct allows for the formation of biomimetic fibrillar
motifs as well as diverse self‐assembled nano‐
morphologies.1e,2 Recent work has shown that polymorphism
in such generic small peptidic architectures is usually dictated
by molecular parameters such as peptide concentration,
nature of the solvent, pH of the medium and the ambient
temperature.2g,3 We believe that active control on the inter‐
conversion of these diverse aggregation states will facilitate
the understanding of the self‐assembly pathways of complex
dipeptides. It will also provide a biocompatible framework to
develop delivery vehicles with triggered release of molecules
at desired cellular targets.2f,3b,4
Figure 1. Photoinduced trans‐to‐cis isomerization in the designed AzoPhe‐Phe‐OH
dipeptide is shown. The optical reversibility between the trans‐cis states can be
achieved by excitation at 365 nm and 457 nm, respectively.
Covalent attachment of photoswitches to peptides and
lipids has been used as a tool to control macromolecular self‐
assembly as well as to develop dynamic biocompatible and
chiroptical materials that are photoactivable.5 In an attempt to
control the morphological diversity of the Phe‐Phe dipeptide
In order to formulate the design principles for light‐triggering
the aggregation of the native FF dipeptide, here we
demonstrate that strategic incorporation of an azo‐
functionality directly on the phenyl side chain can modulate
both the anticipated phenyl‐phenyl hydrophobic packing along
with the H‐bonding network of the backbone. This was
achieved by the design of a novel dipeptide AzoPhe‐Phe‐OH
with the Azo‐group at the para‐position of the N‐terminus
phenyl sidechain as shown in Figure 1. The cis‐trans
isomerization reaction of the azo‐group comprehensively
alters the aggregation propensity of the parent dipeptide.
Although native‐like fibrils are observed from the aggregation
of monomeric trans‐AzoPhe‐Phe‐OH derivative, the photo‐
a. Department of Chemical Sciences, Tata Institute of Fundamental Research,
Mumbai, 400005, India
b. KIIT‐Technology Business Incubator & KIIT‐School of Biotechnology, KIIT
University, Bhubaneswar, Odisha, India .
*Email: dasgupta@tifr.res.in and aseem@kiitincubator.in
†Current address: Center for Free‐ Electron Laser Science (CFEL), Deutches
Elektronen‐Synchrotron DESY, D‐22607, Hamburg, Germany.
Electronic Supplementary Information (ESI) available: Characterization of the
molecule, additional spectroscopic data provided. See DOI: 10.1039/x0xx00000x
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in our preparations (Figure S7 in SI). The UV‐Vis absorption
triggered cis‐monomer does not aggregate even at high
concentrations of the dipeptide. In addition, our design spectrum of trans‐aggregate shows a bathochromic shift of
8
π* transition to 330 nm (ϵ= 4255±266 M‐1cm‐1)
provides a facile and reversible optical handle to drive the
nm in the π

morphology inter‐conversion from fibril‐to‐vesicle.
while n π* transition exhibits a hypochromic shift of

5 nm
to 430 nm (See supporting information Figure S8a, S10).
However in the cis‐form of the monomer, increasing the
concentration up to 8mM in methanol:water mixture did not
induce any aggregation as shown in Figure 2b.
Figure 2. (a) Main: Steady state UV‐Vis absorption spectra of trans and cis monomers
of AzoPhe‐Phe‐OH in methanol (0.18 mM). Inset: The spectral range for the n‐π*
transition is expanded for clarity; (b) DLS measurements reporting the hydrodynamic
radii of the monomer in methanol and aggregate in methanol‐water mixture. Left
panel: Data on trans‐AzoPhe‐Phe‐OH is shown along with an image of the turbid
solution upon aggregation. Right panel: Data on cis‐AzoPhe‐Phe‐OH is shown along
with an image of the clear solution at high concentration (8mM).
Figure 3. SERS spectra represent trans monomer to aggregate transition of AzoPhe‐
Phe‐OH in methanol: water solution (1:12 ratio). SERS measurements were done at
four different concentrations as shown above with Raman excitation at 532 nm.
The synthesis of the molecule AzoPhe‐Phe‐OH was carried
out by diazotization reaction on Boc‐protected L‐p‐
aminophenylalanine to yield Boc‐AzoPhe‐OH that was
subsequently extended to AzoPhe‐Phe‐OH dipeptide using
conventional solution phase peptide coupling reaction as
described in the supporting information. The synthesized
AzoPhe‐Phe‐OH dipeptide was characterized by reverse phase
We used surface enhanced Raman spectroscopy (SERS) to
characterize the structural changes during aggregation of the
monomeric dipeptide as well as probe the aggregate
morphology upon photo‐isomerization. Figure 3 shows the
SERS spectra of the trans‐peptide of four different
concentrations 0.1 mM, 1 mM, 4 mM and 8 mM. The
vibrational modes at 1143 cm‐1, 1183 cm‐1, 1308 cm‐1, 1412
cm‐1, 1443 cm‐1 and 1465 cm‐1 were assigned to both the
1
HPLC along with H‐NMR, 13C‐NMR and ESI‐MS as shown in
Figure S2‐S5 of SI.
In order to characterize the molecular properties of the
designed dipeptide AzoPhe‐Phe‐OH in its two configurational
states, we carried out steady‐state UV‐Vis absorption
spectroscopy of the dipeptide in both monomeric and
aggregated form. Figure 2a shows overlapping but distinct
absorption spectra of both trans‐ and cis‐AzoPhe‐Phe‐OH
dipeptide in its monomeric form in methanol. The absorption
skeletal stretching and bending of the native trans‐azobenzene
31, 32, 34‐36
incorporated in the peptide (Table 1 in SI).
The
vibrational modes at 611 cm‐1, 913 cm‐1, 1002 cm‐1 and 1020
cm‐1 are characteristic of the aromatic ring vibrations from the
Phenylalanine building block.9 The intense bands in the region
1590‐1600 cm‐1 is assigned to the in‐plane C=C stretch
vibrations arising from two distinct phenyl groups.9
spectrum of trans‐isomer shows a strong π
322 nm (molar extinction coefficient, ε
14683 ± 3372 M‐1cm‐1)
and a weak n π* transition near 435 nm. The trans
π* transition near

Raman spectra at low concentrations of the azo‐dipeptide
(0.1 mM, 1mM) show broad vibrational features at 930 cm‐1,
1020 cm‐1 and 1390 cm‐1, respectively. The 1020 and 1390 cm‐1
feature disappears upon aggregation while the spectra in
between 900‐1000 cm‐1 show resolved features. The two
peaks appear at 913 cm‐1 and 931 cm‐1 while at lower
frequency region the modes at 594 cm‐1 and 638 cm‐1 are
observed at high peptide concentrations. The vibrational
modes near 931 cm‐1 and 1390 cm‐1 are assigned to the C‐COO‐

conformation of azobenzene in the dipeptide is thermally
stable than the cis‐isomer hence substantial population of the
cis‐azodipeptide can only be obtained by the irradiation with
365 nm light which involves
excitation). The absorption spectrum of cis isomer shows two
absorption maxima near 289 nm (ε
4120 ± 190 M‐1cm‐1) and
π* and π* transitions
ππ* transition (S0S2

429 nm characteristic of
respectively.
π

n
stretching and COO‐ symmetric stretch of the peptide
9d, 10
backbone respectively.9b,
The COO‐ stretch disappears
The self‐assembly of trans‐AzoPhe‐Phe‐OH is induced by
the addition of water to the methanol in 1:12 v/v (methanol:
water). The solution turns turbid in 10 hours due to formation
of small aggregates as shown in figure 2b. The aggregate size is
assessed by measuring the equivalent hydrodynamic radius
using DLS (dynamic light scattering) method. The DLS shows
the formation of nano‐aggregates of size ~160 nm with a
narrow distribution. The observed critical concentration of the
dipeptide is 150 μM above which nanoaggregates are formed
upon aggregate formation highlighting the burial of the C‐
terminus upon fibril formation. Additionally the narrowing of
the Raman linewidths at high concentrations indicates that the
conformational heterogeneity is reduced as the fibrillar
morphology forms. The evidence for the fibrillar structure
comes from the broad shoulder observed near to 1600 cm‐1,
with less intense modes near 1615 cm‐1, 1640 cm‐1 and 1661
cm‐1 all of which represent the Amide‐I spectral region.9a, 11
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The Amide‐II and Amide‐III vibrations appear at 1545 cm‐1 and trans‐azo‐fibril we observe it at 1640 cm‐1.9b,
Upon UV
1225 cm‐1 respectively.9a, 11 The appearance of modes near the irradiation of the fibril (red trace), the Amide‐I region gets
amide I, amide II and amide III shows that the dominant modified to a sharp transition at 1645 cm‐1 while characteristic
secondary structure has anti‐parallel β‐sheet conformation.9a, vibrational feature of cis azo benzene peaks appear at 611 cm‐
11 The observed secondary structure arrangement is similar to 1, 772, 1512 cm‐1 (described under Table 2 in SI).12 The peak
the molecular level description of oligomeric amyloid corresponding to Cα‐H bending in the peptide backbone is
structures.1f The covalent attachment of azobenzene group in absent in the trans aggregate, but a significant band at 1362
its trans‐configuration therefore does not inhibit the cm‐1 is seen after trans‐to‐cis photo‐isomerization of the
aggregation, on the contrary it accelerates the fibrillation aggregate which is reported in literature as coupling of Cα‐H
propensity of the free dipeptide.
bending to the C‐N stretching and N‐H bending modes of
To test the hypothesized azo‐induced hydrophobic and H‐ peptide backbone upon conformational change.11 The Raman
bonding destabilization upon photo‐isomerization, we spectrum of the vesicle was thus characterized by formation of
investigated the aggregation of the azo‐dipeptide in its cis‐ turns and coil as the Amide‐I feature is sharp along with small
isomer. Surprisingly, the cis‐isomer of peptide in feature at 1690 cm‐1. 1f, 9a, 10c, 11
methanol:water solvent mixture does not undergo aggregation
even at high peptide concentration (8 mM) and the peptide
solution remains clear (inset image in Figure 2b). We also do
not observe any absorption changes at that concentration
suggesting absence of any aggregates in this molecular form of
the dipeptide. DLS measurements show that the size
distribution (right panel Figure 2b) is similar to the molecule in
its monomeric form at low concentrations, indicating the cis‐
isomeric form of the dipeptide does not favour self‐assembly.
Our observation implies that the poor packing of the aromatic
phenyl side‐chains due to N=N distortion in the cis‐form
prevents the self‐assembly of the phenylalanine dipeptide in
water. Although hydrophobic collapse for the Phe side‐chains
is favorable in water, the significance of establishing good
packing and additionally the H‐bonding contacts in the initial
stages of aggregate formation is highlighted here.
In order to understand whether the trans‐to‐cis induced
structural change in the fibrillar backbone affects the
Figure 4. (Top) TEM image showing the morphology of the self‐assembled peptide in
morphology, we irradiated the fibrils with 365 nm light for 15
trans isomeric form and the vesicular morphology of the peptide assembly after UV
irradiation on the fibril. (Bottom) SERS spectra of aggregated FF dipeptide (black),
min and tracked the morphology changes in aggregates using
optical spectroscopy and TEM. The trans‐to‐cis photo‐ aggregated trans‐AzoPhe‐Phe‐OH (blue) fibril and the vesicular form after illumination
(red).
isomerization of the azo‐functional group within the aggregate
shows a red shift in π ‐ π* transition of azo‐functional group as
To elucidate the mechanistic pathway of the fibril‐to‐
vesicle structural transition, we performed time‐lapsed SERS at
different timescales subsequent to UV excitation (see Figure
S11, S12). Significant changes in the vibrational features are
observed after 15 min of UV irradiation while Raman spectra
remain intact at later timescales once the cis‐form is
established. We did not observe any structural intermediates
during the morphology switching from fibril‐to‐vesicle (Figure
S11, S12 in SI). The absence of photo‐intermediates along with
SERS detection of the aggregated fraction helps to conclude
that cis‐form creates local defect in the fibril leading to subtle
reorganization of the fibrillar architectures (See Figure S14 in
SI). This can be contrasted to the previously reported
observation in the aggregated AMPP peptide where cis‐form
lead to breakage of the fibrils as the azo‐group was part of the
backbone itself.5b, c Additionally, recent work by Nilsson and
co‐workers showed that if the Azo switch is positioned in the
turn region of Amyloid‐β peptide the fibrils turn into
amorphous aggregates which are not toxic.13 In our case, the
conformational switching in AzoPhe‐Phe‐OH however disturbs
compared to monomer of cis‐isomer, while n ‐ π* transition
has a maxima at 435 nm (Figure S8a in SI). The quantum yield
of trans‐to‐cis isomerization of aggregate is 0.49 (Figure S10 in
SI). The TEM also reports for a clear fibril‐to‐vesicle transition
with the vesicles showing heterogeneous sizes. The vesicle
morphology can be switched back to fibril upon cis‐to‐trans
photo‐isomerization of azo moiety within aggregated peptide
using 457 nm LED illumination (Figure S13 in SI) and the
quantum yield for cis‐to‐trans reverse isomerization of
aggregate is 0.38 (Figure S10 in SI). The observed photo‐
reversibility is one of the most exciting features of our azo‐
dipeptide design.
SERS measurements were used to confirm the formation of
cis‐products within the aggregates and its effects on the
molecular packing. Figure 4a, b show the comparative Raman
vibrational features of the fibril, the vesicle and the self‐
assembled unmodified Phe‐Phe dipeptide. The Amide‐I
vibrations were used to probe sensitively the peptide
secondary structure in its aggregated state. For Phe‐Phe
dipeptide the Amide‐I is observed at 1632 cm‐1 while for the
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Notes and References
the FF hydrophobic packing, thereby leading to creation of
bends in peptide backbone to drive vesicular structure.
Figure 5 illustrates the schematic model explaining the
control on the assembly pathway as well as the mechanism of
vesicle formation from fibril. The peptide AzoPhe‐Phe‐OH in
trans isomeric form shows more propensity to form fibril as
compared to Phe‐Phe dipeptide as shown in the figure by a
green arrow. The peptide AzoPhe‐Phe‐OH in cis isomeric form
does not undergo self‐assembly due to conformational
preferences of the cis azo functional group, and therefore a
barrier exists in the aggregation coordinate. The trans‐to‐cis
photo‐isomerization of the azo functional group in the
aggregated peptide switches the morphology from fibril to
vesicle, and vesicle morphology can be reversibly switched to
fibril upon 457 nm excitation along the isomerization
coordinate.
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The authors thank Dr. C. Narayana and Mr. S. Aggarwal (JNCASR,
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Graphical abstract
Covalently modified trans‐AzoPhe‐Phe‐OH dipeptide shows
reversible photo‐switching between its native fibril and vesicle
aggregate morphology.
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