Helical Sulfono-γ-AApeptides with Aggregation-Induced Emission and Circularly Polarized Luminescence

Article abstract of DOI:10.1021/jacs.9b05329

Aggregation-induced emission (AIE) was intensively studied because of packing of small molecules and polymers; however, mid-molecular-weight (1000-3000) molecular scaffold containing a precise number of AIE luminogens is rare. Herein, we report the investigation of three tetraphenylethylene (TPE)-modified sulfono-γ-AApeptides in which multiple TPE moieties are conjugated to the chiral right-handed helical peptidomimetic backbone as functional side chains. The crystal structure of the TPE-α/sulfono-γ-AA peptide 1 demonstrates that because of the rigid helical scaffold of the TPE-α/sulfono-γ-AA peptides, the intramolecular rotations of the TPE with short linker are restricted, therefore leading to the boosted fluorescent emission in solution. Peptides 2 and 3 exhibit aggregation-induced emission enhancement (AIEE), possibly because of the combination of both AIE and rotation restriction. Moreover, because of their preoriented assembly induced by the right-handed helical scaffold, these emissive chiral luminogens show effective circularly polarized luminescence signals with high dissymmetry factor g_lum. Finally, the amphiphilic nature of TPE-α/sulfono-γ-AA peptides could enable them to penetrate the bacterial membranes and exhibit strong fluorescence. Their antimicrobial activity and labeling-free character could further augment their potential applications in both materials and biomedical sciences.

Full text of DOI:10.1021/jacs.9b05329

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Article
Helical Sulfono-#-AApeptides with Aggregation-Induced
Emission and Circularly Polarized Luminescence
Yan Shi, Guangqiang Yin, Zhiping Yan, Peng Sang, Minghui Wang, Robert Brzozowski,
Prahathees Eswara, Lukasz Wojtas, You-Xuan Zheng, Xiaopeng Li, and Jianfeng Cai
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b05329 • Publication Date (Web): 23 Jul 2019
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Helical Sulfono-γ-AApeptides with Aggregation-Induced Emission and
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Circularly Polarized Luminescence
Yan Shi,1,¶ Guangqiang Yin,1,¶ Zhiping Yan,3 Peng Sang,1 Minghui Wang,1 Robert Brzozowski,2 Pra-
hathees Eswara,2 Lukasz Wojtas,1 Youxuan Zheng,3,* Xiaopeng Li,1,* and Jianfeng Cai1,*
1 Department of Chemistry, University of South Florida, 4202 East Fowler Avenue, Tampa, Florida 33620,
United States.
2 Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, 4202
East Fowler Avenue, Tampa, Florida 33620, United States.
3 State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Nan-
jing University, 210023 Nanjing, China.
ABSTRACT: Aggregation-induced emission (AIE) was intensively studied owing to packing of small molecules and polymers,
however, mid-molecular-weight (1000-3000) molecular scaffold containing precise number of AIE luminogens is rare. Herein
we report the investigation of three tetraphenylethylene (TPE) modified sulfono-γ-AApeptides, in which multiple TPE moie-
ties are conjugated to the chiral right-handed helical peptidomimetic backbone as functional side chains. The crystal structure
of the TPE-α/sulfono-γ-AA peptide 1 demonstrates that due to the rigid helical scaffold of the TPE-α/sulfono-γ-AA peptides,
the intramolecular rotations of the TPE with short linker are restricted, therefore leading to the boosted fluorescent emission
in solution. Peptides 2 and 3 exhibit aggregation-induced emission enhancement (AIEE), possibly owing to combination of
both AIE and rotation restriction. Moreover, due to their pre-oriented assembly induced by the right-handed helical scaffold,
these emissive chiral luminogens show effective circularly polarized luminescence signals with high dissymmetry factor glum
.
Finally, the amphiphilic nature of TPE-α/ sulfono-γ-AA peptides could enable them to penetrate the bacterial membranes and
exhibit strong fluorescence. Their antimicrobial activity and labeling-free character could further augment their potential
applications in both materials and biomedical sciences.
Introduction
by covalent bond connection1g and coordination networks9
so as to enhance fluorescence intensity. Instead of aggrega-
tion and packing, it is rare to turn on luminescent properties
of TPEs at the single molecular level, e.g. in solution.10
The development of aggregation-induced emission (AIE)
materials has recently drawn considerable attention due to
their applications in OLEDs, bioprobes, chemosensors, chi-
ral recognition and so on.1 Among the prototypical AIE lu-
minogens (AIEgens), the tetraphenylethylene (TPE) deriva-
tives are the most classic family and have been extensively
In parallel to the intensive studies of AIE, circularly polar-
ized luminescence (CPL) materials have also attracted in-
creasing interests as circularly polarized light would im-
prove the quality of the 3D image and decrease the damage
to the eyes in display.11 In the past years, the research inves-
tigation based on chiral luminescent systems has made sig-
nificant progress, including metal complexes,12 small or-
ganic luminophores,13 conjugated polymers,14 supra-
molecules,15 and liquid crystals.16 But except for the lantha-
nide complexes, most reported systems still suffered from
2
explored. In these emissive systems, the TPE derivatives
were incorporated into the metal−organic frameworks
(MOFs),3 covalent organic frameworks (COFs),4 metallo-
macrocycles,5 polymers,6 and metallo-cages.2b, 7 However,
most of the designs are based on a same tactic, that is, the
restriction of the intramolecular rotation (RIR) due to ag-
gregation and packing of TPE moieties.1f, 8 Upon aggregate
formation, confinement of the rigid environment weakens
the rotation of the four peripheral aromatic rotors against
the central olefin stator in TPE, leading to the suppression
of nonradiative decay pathways and the activation of the ra-
diative decay in solid state.1f On this basis, lots of efforts
have been made to restrict the rotation of the phenyl rings
the relatively low luminescence dissymmetry factor (glum
)
both in solution and solid state, ill-defined structure-prop-
erty relationship, and chiroptical properties sensitive to the
external environments. Therefore, it is still urgent to ex-
ploit material which could directly generate CPL,
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particularly design and synthesis of a single molecule bear-
ing CPL function rather than through the packing of mole-
cules.
sulfono-γ-AA peptides as well as solution structures.18,19 We
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hypothesized that when conjugated with the TPE moiety,
the constrained helical backbone of the sulfono-γ-AA pep-
tide would restrict the intramolecular rotation of the TPE,
thereby inducing the fluorescence of these TPE conjugated
sulfono- γ-AA peptides even at the single molecular level in
solution. In addition, due to chiral arrangement/assembly
of the TPE moieties induced by the right-handed helical
sense of the molecular scaffold, these TPE-α/sulfono-γ-AA
peptides would also be expected to exhibit good CPL prop-
erties, which are generated at single molecule level instead
of intermolecular packing.
To tackle the challenges existing in both AIE and CPL,
herein we report the properties of TPE modified 1:1 α/sul-
fono γ-AApeptides. The γ-AApeptide (oligomers of γ-substi-
tuted-N-acylated-N-aminoethyl amino acids) is a new class
of the peptidomimetics, the backbone of which was inspired
by the chiral PNA.17 In the 1:1 α/sulfono-γ-AA peptides, the
bulky sulfonamide groups induce a curvature conformation
of the backbone, leading to the formation of robust right-
handed 413 windmill-shaped heliacal structures, which are
confirmed by the crystal structure of homo/heterogeneous
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Figure 1. Chemical and crystal structure of TPE-α/sulfono-γ-AA peptide 1, the crystal structures are drwan by PyMol. A). Chemical
structure and the 13-atom-hydrogen-bonding pattern. B). Crystal structure of the bonding pattern. C). Helical cartoon of the crystal
structure. D). Crystal packing of 1 along the peptide axis. E). Cartoon structure of D. F). Packing mode of the crystal.
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Results and Discussion
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solution because the seven TPE moieties are constrained on
The first TPE-α/sulfono-γ-AA peptide 1 (Figure 1A) was de-
signed by conjugation of TPEs directly onto the backbone of
the 1:1 α/sulfono-γ-AA hybrid peptide. Particularly, TPE
moieties were incorporated into sulfono-γ-AA building
blocks and the TPE-conjugated 1:1 α/sulfono-γ-AA hybrid
peptide 1 was obtained with decent yield by the solid-phase
standard Fmoc chemistry based on our previous protocol.17
The Crystal showed a 13-atom-hydrogen-bonding pattern,
with 2.7 Å and 3.1 Å hydrogen-binding distance. The persis-
tent and unified intramolecular H-bond network and orga-
nized packing of side chain unambiguously indicates that
this class of oligomers, as a 413 helix, could provide a partic-
ularly strong stabilization of this novel secondary structure
motif (Figure 1A, S1). To our delight, TPE-α/sulfono-γ-AA
peptide 1 was successfully solved by the single-crystal X-ray
crystallography with resolutions of 1.5 Å. In the crystal
structure, it shows that peptide 1 adopts right-handed heli-
cal conformation, with a diameter of 6.0 Å and pitch of 5.8 Å
which are consistent to our previous reported related struc-
tures.18a There are exactly four side chains per helical turn,
and TPE groups are present in a right-handed helical sense
(Figure 1B-C). This led to a pseudo- four-fold symmetry of
windmill-shape on the top view (Figure 1D-F).
the helical scaffold. And such fluorescence enhancement is
due to their rotation limitation rather than aggregation in-
duced emission. To test our hypothesis, we next carried out
absorption and fluorescence studies. As shown in Figure
2B, two strong peaks (250 nm and 350 nm) in the UV-vis
spectrum of TPE-α/sulfono-γ-AA peptide 1 were observed
as the typical absorption peaks of TPE moieties,9 indicating
that conjugation of TPE moieties to the helical peptide did
not alter their intrinsic absorptive property. The result
prompted us to move forward to study their potential fluo-
rescent activity. The TPE-α/sulfono-γ-AA peptide 1 (Figure
2C) was found to be soluble in pure water, however, 99%
PBS (Phosphate Buffered Saline) buffer is a poor solvent
which led to the precipitation of 1 due to enhanced salt
strength. It is very interesting that 1 exhibits strong fluores-
cence in pure water (Figure 2A), consistent to our postula-
tion that helical molecular scaffold restricts the free rota-
tion of TPE moieties, leading to significantly enhanced fluo-
rescence even in solution. When the percentage of poor sol-
vent PBS buffer fraction (fPBS) is gradually increased from
0% to 99%, the fluorescence intensity shows no significant
change (Figure 2A and 2D), with good quantum yield (ΦF =
35%). It suggested that boosted fluorescence was due to re-
striction on TPE bond rotation instead of AIE.
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On the basis of helical structures, we postulated that 1 could
exhibit fluorescence at single molecular level even in
Figure 2. A). Photographs of 1 in water/PBS with various PBS fractions. B). UV/Vis spectra of 1 in water/PBS with various PBS
fractions; C). Fluorescence spectra (λex = 325 nm, c = 5.0 μM); D). Quantum yields.
flexibility of side chains and electrostatic charge repulsion.
To understand whether the stability of helical scaffold has
impact on the fluorescent behavior of the TPE modified
α/sulfono-γ-AA peptide, a new sequence 2 was also synthe-
sized, in which the alanine residues in 1 was replaced with
Thus, we anticipated that the introduction of these amino
side chains could confer TPE moieties with increased rota-
tional freedom. Interestingly, although similar absorption
and emission wavelengths were found in 2 (Figure 3B-D), 2
lysine residues (Figure 3A). Bearing amino side chains, 2 is
displayed different fluorescent behaviors compared to the
expected to destabilize the helical scaffold due to the
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steady emission of 1 in both solutions and aggregation repulsion could be shielded by PBS salts, which significantly
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states. As shown in Figure 3E, the TPE-α/sulfono-γ-
AApeptide 2 starts with a low ΦF value (5%) in pure water,
which may be due to the electrostatic repulsion of positively
charge side chains that destabilize the helical scaffold. How-
ever, when the fPBS increased from 0% to 10%, even though
the sequence was still completely soluble, the charge
enhanced the helical stability, leading to sharply increased
ΦF (35%). Further increase of PBS led to gradual aggrega-
tion of TPE-α/sulfono-γ-AApeptide 2 with enhanced quan-
tum yield up to 45%. This is a typical AIE effect, by which
aggregation further stabilized the helical structure and mo-
lecular packing, thereby enhancing fluorescence intensity.
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Figure 3. A). The structure of 2. B). Photographs of 2 in water/PBS with various PBS fractions. C). UV/Vis spectra of 2 in water/PBS
with various PBS fractions; D). Fluorescence spectra (λex = 325 nm, c = 5.0 μM); E). Quantum yields.
20%), AIE took a more significant role than 2, as seen for
the ΦF values at different fw which demonstrated a gradual
After we explored the impact of helical scaffold on the fluo-
increment and reached the maximum (ΦF = 79 %) at fPBS
=
rescence of TPE-α/sulfono-γ-AA peptides, we next asked if
further induction of rotational freedom of TPE moieties
could tune fluorescence behavior. As shown in Figure 4, a
new sequence 3 was prepared. Unlike 1 and 2, in which TPE
moieties were conjugated to the backbone via sulfonyl
group directly, the TPE moieties in the peptide 3 were at-
tached by the amide bond via an additional flexible ethyl
sulfonyl linker (Figure 4A). As anticipated, although helical
molecular scaffold still gave fluorescence at 0% PBS (ΦF =
60% (Figure 4E). We speculated that when TPE moieties
were attached to the helical scaffold via a relatively longer
and flexible linker, the restriction from the backbone be-
came weaker, and as such the ΦF was low when fPBS was
close to zero. It is worth noting that, as fPBS increased, the
fluorescence is boosted up through the combination of both
helical scaffold stabilization as well as aggregation induced
emission enhancement (AIEE).20
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Figure 4. A). The structure of 3. B). Photographs of 3 in water/PBS with various PBS fractions. C). UV/Vis spectra of 3 in water/PBS
with various PBS fractions; D). Fluorescence spectra (λex = 325 nm, c = 5.0 μM); E). Quantum yields.
To further investigate the emission properties of TPE-
α/sulfono-γ-AA peptides 1-3, we studied their aggregation
behaviors by dynamic light scattering (DLS) and transmis-
sion electron microscopy (TEM). As shown in Figure 5, the
TPE-α/sulfono-γ-AA peptides 1-3 were prone to forming
nanosphere particles in solution. From the DLS results (Fig-
ure 5A-C), the average hydrodynamic diameters (Dh) of the
TPE-α/sulfono-γ-AA peptides 1-3 nanospheres increased
from 8.5, 5, 4 nm (0% PBS) to 15, 8, 7 nm (50% PBS), 18, 25,
8 nm (99% PBS). TEM was subsequently performed to fur-
ther investigate the aggregation behavior of peptides. As
shown in Figure 5D, the images of peptide 1 revealed that
the size of these particles did not increase significantly with
the Increment of PBS fraction, indicating that the helical
structure took the predominant role in emission inducing,
which was consistent with the result of the quantum yield.
While for TPE-α/sulfono-γ-AA peptides 2 and 3 (Figure 5E,
F), at 0% PBS in water, there is no obvious aggregated par-
ticle. But along with the increment of the PBS, the size and
intensity of the particles became enlarged. These results are
in good agreement with the observation that at higher per-
centage of PBS the emission was enhanced by the aggrega-
tion. Furthermore, at each PBS percentage of TPE-
α/sulfono-γ-AA peptides 1-3, the size of around 100 parti-
cles was measured by Image J, and the aggregate diameter
distribution data was consistence with the DLS and TEM ex-
periments (Figure S2).
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Figure 5. A-C DLS data and D-F TEM images of TPE-α/sulfono-γ-AA peptides 1-3 aggregates in 0% PBS, 50% PBS and 99% PBS
(scale bar, 500 nm for D, E, F upper images and 100 nm for D, E, F, bottom images, respectively).
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Figure 6. A). The CD spectra of the TPE-α/sulfono-γ-AA peptides 1-3 in H2O/PBS 1:1. B-D). The CPL spectra of peptides 1-3 in PBS
buffer percentage.
The circular dichroism (CD) spectra were next performed in
H2O/PBS (1:1) in the range of 195 - 260 nm in order to eval-
uate the helical propensity of the three peptides in solution.
As shown in Figure 6A, all peptides show strong positive
cotton effects between 205- 215 nm, suggesting that the
TPE-α/sulfono-γ-AA peptides 1-3 adopt similar right-
handed helical conformations.18a Interestingly, further CD
study of peptide 2 at different solvent systems suggested
that the sequence retained a good degree of helicity in the
presence of water, while in other solvent system the cotton
effect became relatively weaker (Figure S3).
change dramatically of TPE-α/sulfono-γ-AA peptide 2-3
(Figure 6B-D). We speculate that these CPL helical folda-
mers are superior to known CPL small molecules and poly-
mers, since polymers do not have defined structure
whereas it is challenging to precisely control the packing of
small chiral molecules.
The peptides 2 and 3 contains both cationic and hydropho-
bic groups, which satisfy the rationale for developing anti-
microbial peptidomimetics mimicking host-defense pep-
tides (HDPs): the cationic functional groups would bind to
the negatively charged bacterial membranes, and the hy-
drophobic groups could subsequently lead to the disruption
of the bacterial membranes.22 Based on this assumption, we
postulated that these two peptides would have antimicro-
bial activities. Indeed, 2 and 3 show IC50s of 3.2 and 6.3
µg/mL in killing Gram-positive bacteria Methicillin-re-
sistant S. aureus (Staphylococcus aureus, MRSA). MRSA is a
significant opportunistic pathogen which is responsible for
most hospital-acquired infection in the world.23 As ex-
pected, peptide 1 did not show any antibacterial activity.
Compounds bearing both fluorescence and bacteria-killing
function could be developed for both diagnostic and antibi-
otics. Furthermore, as peptides 2 and 3 display strong
Given the fact that these TPE moieties are arranged on the
right-handed helical scaffold, and the chirality could be
transferred from the chiral backbone of the γ-AApeptides,
we envision that these luminous TPE-α/sulfono-γ-AA pep-
tides would also generate CPL. To our delight, in the test of
three sequences in different ratios of water/PBS buffer, in-
tensive CPL signals were observed in all the samples. The
highest calculated value of the dissymmetry factor (glum) is
ca. 1.2 ×10-2, which is a large glum data compared with the
reports (10-5-10-3 order).21 In the TPE-α/sulfono-γ-AA
peptide 1, the glum data is increasing accompanied by the in-
creased PBS buffer percentage, while the glum data does not
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autofluorescence, we studied their localization and antibac- membrane-binding. Similarly, peptides 2 and 3 appeared
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terial activity through three dimensional, high-resolution,
live-cell, fluorescence microscopy. Briefly, we treated the
cells of Gram-positive S. aureus and Bacillus subtilis as well
as Gram-negative Escherichia coli with the TPE-α/sulfono-
γ-AA peptides 2 or 3 at the concentration of 0.05 mg/mL
(1X), 0.25 mg/mL (5X), and 0.5 mg/mL (10X). Cells treated
with the vehicle, dimethyl sulfoxide (DMSO), served as our
negative control. As shown in Figure 7, S. aureus was sensi-
tive to the treatment of peptides 2 or 3, as indicated by the
loss of cell shape, integrity, and lysis, at the concentrations
of 5X and higher. At lower concentrations, the localization
of both peptides around the cell periphery was evident, sug-
gesting their antimicrobial property likely stems from
to localize to the cell membrane in B. subtilis, although cells
were resistant to the peptide treatment as they were able to
retain their cell shape and became sensitive only at 10X or
higher concentrations. In E. coli, TPE-α/sulfono-γ-AA pep-
tide 2 did not target to the cell surface and peptide 3 weakly
associated with the cell periphery. E. coli cells were also re-
sistant to peptide 2 treatment and were sensitive to pep-
tide 3 only at higher concentrations. Thus, TPE-α/sulfono-
γ-AA peptides 2 and 3 are potent anti-staphylococcal
agents.
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Figure 7. Micrographs of S. aureus, B. subtilis, and E. coli cells treated with 0.05 mg/mL (1X), 0.25 mg/mL (5X), and 0.5 mg/mL (10X)
of TPE-α/sulfono-γ-AA peptides 2 or3. The vehicle for the peptides, DMSO, was used as a control. Differential interference contrast
(DIC) and the autofluorescence of peptides obtained through standard DAPI filter are shown. Scale bar, 1 µm.
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Tuning of Crystallization-Induced Emission and Introduction into
Conclusion
the Main Chain of Conjugated Polymers. J. Am. Chem. Soc.2014, 136
, 18131-18139; (f) Mei, J.; Leung, N. L. C.; Kwok, R. T. K.; Lam, J. W.
Y.; Tang, B. Z., Aggregation-Induced Emission: Together We Shine,
United We Soar! Chem. Rev. 2015, 115, 11718-11940; (g) Xiong, J.-
B.; Feng, H.-T.; Sun, J.-P.; Xie, W.-Z.; Yang, D.; Liu, M.; Zheng, Y.-S.,
The Fixed Propeller-Like Conformation of Tetraphenylethylene
that Reveals Aggregation-Induced Emission Effect, Chiral
Recognition, and Enhanced Chiroptical Property. J. Am. Chem.
Soc.2016, 138, 11469-11472; (h) Zheng, J.; Ye, T.; Chen, J.; Xu, L.; Ji,
X.; Yang, C.; He, Z., Highly sensitive fluorescence detection of
1
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In this work, we designed and prepared a series of novel chi-
ral and emissive TPE conjugated sulfono-γ-AApeptides. By
investigating the structure and the properties, we identified
that the helical peptide backbone provides a favorable scaf-
fold to restrict the intramolecular rotations and induce flu-
orescence. The fluorescence could be synergistically en-
hanced by AIE effect. In addition, the right-handed helical
framework could be used to precisely arrange the distribu-
tion of TPE moieties, which lead to the large CPL dissym-
metric factor as high as 1.2  10-2, augmenting their great
potential in chiral recognition and enantioselective cataly-
sis. The autofluorescence property could be adopted for the
investigation of mechanism of antimicrobial action.
9
heparin based on aggregation-induced emission of
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ASSOCIATED CONTENT
Supporting Information.
“This material is available free of charge via the Internet at
http://pubs.acs.org.”
Synthetic routes, characterization data, X-ray crystallographic
data, HPLC traces, additional figures.
AUTHOR INFORMATION
Corresponding Author
* jianfengcai@usf.edu
xiaopengli1@usf.edu
yxzheng@nju.edu.cn
Author Contributions
¶ These authors contributed equally to this work.
Notes
4. (a) Zhou, T.-Y.; Xu, S.-Q.; Wen, Q.; Pang, Z.-F.; Zhao, X., One-Step
Construction of Two Different Kinds of Pores in a 2D Covalent
Organic Framework. J. Am. Chem. Soc.2014, 136, 15885-15888; (b)
Ascherl, L.; Sick, T.; Margraf, J. T.; Lapidus, S. H.; Calik, M.; Hettstedt,
C.; Karaghiosoff, K.; Döblinger, M.; Clark, T.; Chapman, K. W.; Auras,
F.; Bein, T., Molecular docking sites designed for the generation of
highly crystalline covalent organic frameworks. Nat. Chem. 2016,
8, 310; (c) Dalapati, S.; Jin, E.; Addicoat, M.; Heine, T.; Jiang, D.,
Highly Emissive Covalent Organic Frameworks. J. Am. Chem. Soc.
2016, 138, 5797-5800.
The authors declare no conflict of interest.
ACKNOWLEDGMENT
The work was supported by NSF 1708500 (JC), NIH
1R01GM112652-01A1 (JC).
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