Reversible, short α-peptide assembly for controlled capture and selective release of enantiomers

Article abstract of DOI:10.1021/jacs.6b02401

Although significant progress has been achieved with short peptide nanostructures, the construction of switchable membrane assemblies remains a great challenge. Here we report short α-peptide assemblies that undergo thermo-reversible switching between assembly and disassembly states, triggered by the conformational change of laterally grafted short peptides from a folded α-helix to a random coil conformation. The α-helical peptide based on two oligoether dendron side groups forms flat disks, while the peptide helix based on three dendron side groups forms hollow vesicles. The vesicular membrane can spontaneously capture a racemic mixture through the self-formation of vesicular containers upon heating and enantioselectively release the chiral guest molecule through preferential diffusion across the vesicular walls.

Full text of DOI:10.1021/jacs.6b02401

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Communication
Reversible Short #-Helical Peptide Assembly for
Controlled Capture and Selective Release of Enantiomers
Xi Chen, Ying He, Yongju Kim, and Myongsoo Lee
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b02401 • Publication Date (Web): 14 Apr 2016
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Journal of the American Chemical Society
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Reversible Short α-Helical Peptide Assembly for Controlled Capture
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and Selective Release of Enantiomers
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Xi Chen, Ying He, Yongju Kim,* and Myongsoo Lee*
State Key Lab of Supramolecular Structure and Materials, College of Chemistry, Jilin University, Changchun 120031, China
Supporting Information Placeholder
an α-helical conformation through aggregation of the β-sheet pep-
tides.
ABSTRACT: Despite significant progress has been achieved on
short peptide nanostructures, the construction of switchable mem-
brane assemblies remains a great challenge. Here we report short
α-peptide assemblies that undergo thermo-reversible switching
between assembly and disassembly states triggered by the con-
formational change of laterally-grafted short peptides from a fold-
ed α-helix to a random coil conformation. The α-helical peptide
based on two oligoether dendron side groups forms flat disks
while the peptide helix based on three dendron side groups forms
hollow vesicles. In particular, the vesicular membrane can spon-
taneously capture a racemic mixture through the self-formation of
vesicular containers upon heating and enantioselectively release
the chiral guest molecule through preferential diffusion across the
vesicular walls.
6
Short peptides that self-assemble into nanostructures are of
enormous interest for biological, medical, and biotechnological
applications because the design of model peptides exhibiting a
high tendency for self-assembled structure formation proved to be
1
an ideal target for mimicking biological activities of proteins.
The formation of well-defined peptide assemblies depends criti-
cally not only on their amino acid sequence but also on their fold-
ed secondary structure. Such assemblies include tubules from
2
3
cyclic peptides, porous cages from three-armed peptides, nano-
Figure 1. Molecular structures of peptides 1, 2 and 3. Schematic
representation of their reversible self-assembly; a nanodisk of
peptide 2 and a vesicle of peptide 3.
4
fibers from sequence-controlled short peptides, vesicles from
linear block co-peptides, toroids from cyclic block co-peptides,
5
6
7
and nanosheets from collagen mimic short peptides . However,
the formation of nanostructures by the self-assembly of such short
peptides is mostly based on a β-sheet arrangement of peptide mo-
tifs because the folding of short peptides into an α-helical struc-
ture is accompanied by large entropic cost related to the folding of
However, most of the short α-peptides are far from dynamic
conformational switching between random coil and helical states
which are essential for generating switchable peptide nanostruc-
tures because the helical conformation is stabilized by covalent or
1
0-
8
non-covalent bond stitching incompatible with dynamic motion.
short peptide chains.
1
5
Therefore, the challenging target in peptide assembly based on
Stabilizing the folded forms of short α-peptides is thus prereq-
α-helical peptides is how to confer dynamic switching functions
with their conformations. Considering that the structural trans-
formations of proteins originate from the conformational change
of the peptide chains, the design of short α-helical peptides that
uisite for the peptide chains to assemble into desired nanostruc-
16
9
tures. Methods achieved to stabilize α-helical structures include
1
0
11
covalent bridging amino acid side chains, metal chelates, helix
17
1
2
13
nucleation, and molecular crowding. In addition to these strat-
egies, cyclization of peptides was also proved to be an efficient
approach to stabilizing an α-helical structure through reducing
exhibit high tendencies for medium-induced conformational
changes is anticipated to be an ideal target for the construction of
dynamic peptide nanostructures. To address this challenge, we
considered that lateral grafting of a short α-helical peptide with
oligoether dendrons would drive a random coil conformation to
fold into an α-helical structure which, in turn, self-assembles into
well-defined peptide nanostructures due to thermal dehydration of
oligoether chains. The thermal dehydration of oligoether side
chains would enforce random coil peptide backbones to adopt a
helical conformation through enhanced hydrophobic interactions
1
4
conformational entropic penalty associated with chain folding.
We have demonstrated that macrocyclization of the linear peptide
precursors with a random coil conformation enforces the peptide
1
4
chains to adopt an α-helical structure. The resulting helical pep-
tides self-assemble into undulated nanofibers through 1-
dimensional stacking of elementary micelles. We have also shown
that cyclization of short peptides through a β-sheet linker induces
18
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between oligoether side chains and peptide backbones to mini-
dendrons. Indeed, the temperature-dependent transmittance of the
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mize water influence on α-helical peptide hydrogen bonds. Fur-
thermore, the lateral grafting would drive the induced α-helical
peptides to align parallel to the 2-dimensional plane to form ani-
sotropic membrane structures with helical voids between the heli-
aqueous solutions of both the peptides showed a sharp phase
o
transition at about 45 C (Figure S4), indicating that the ethylene
oxide chains with open conformations are dehydrated to collapse
upon heating (Figure S5).
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cal peptide chains.
The stabilization of the α-helical conformation upon heating
Here, we report reversible α-peptide nanodisks and vesicles
based on flat membrane assembly of α-helical peptides that un-
dergo reversible switching between assembly and disassembly
states triggered by a thermal switch (Figure 1). The self-
assembled structures consist of the lateral association of rod-like
α-helical peptides which allow the assembly to function as an
enantioselective membrane. In particular, the hollow vesicles can
spontaneously capture a racemic mixture through the self-
formation of membrane walls in response to a thermal signal and
enantioselectively release the captured molecule through
preferential diffusion across the vesicular walls. The α-helix-
can be understood by considering peptide-water interac-
1
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tions.
The dehydrated oligoether dendrons would interact
strongly with the hydrophobic residues such as alanine and phe-
nylalanine of the peptide backbone to reduce water accessible
surface area. Additionally, the ether oxygens of the dendritic
chains would also strongly interact with charged lysine. These
interactions provide the shielding effect of the oligoether den-
drons on peptide-water interactions to minimize the water influ-
ence on peptide hydrogen bonds, which triggers stabilization α-
helices upon heating. This is further supported by the higher CD
intensity at 222 nm in peptide 3 with higher volumn fraction of
oligoether dendron than that of peptide 2, indicating that more
oligoether dendrons stabilize α-helices more efficiently, consistent
with the shielding effect of the oligoether dendrons on peptide-
water interactions.
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forming peptides consist of a KKK(FAKA) FKKK amino acid
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21
sequence with high helix propensity. To endow thermo-
responsive feature with the peptide chain, oligoether dendrons
were symmetrically grafted into the peptide chain through click
chemistry of lysine residues with an oligoether dendron (Figure
S1 and S2) . The building blocks were synthesized by a solid state
peptide synthesis method with a combination of both natural ami-
no acids and a dendron-grafted lysine. Peptide 1 with a lack of
oligoether dendrimer adopts a random coil conformation, as con-
firmed by circular dichroism (CD) measurements, irrespective of
temperature change (Figure S3). The α-helical conformation of
peptide 1 could be stabilized only in the presence of a stabilizing
agent, 2,2,2-trifluoroethanol (TFE).
Figure 2. (a) CD spectra of the peptide 2 in 5 mM aqueous KF
solution with various temperatures. (b) CD spectra of the peptide
3 in 5 mM aqueous KF solution with various temperatures.
Figure 3. (a) TEM image of peptide 2 in 5 mM aqueous KF solu-
o
tion at 50 C. (b) Cryo-TEM image of peptide 2 in 5 mM aqueous
o
KF solution at 50 C. (c) AFM image and the height profile along
the white line (3.2 nm). (d) Schematic representation of the disk
assembly of peptide 2.
In great contrast, the incorporation of oligoether dendrons into
the peptide chains drives the random coil conformation of the
peptides to switch into an α-helical conformation above a certain
temperature (Figure 2). At room temperature, the CD spectrum of
peptide 2 containing two dendrons as side groups shows a strong
minimum at approximately 196 nm, indicating that the peptide
adopts predominantly a random coil conformation. Upon heating
We envisaged that the laterally-grafted rod-like α-helical
peptides would be aligned parallel to each other to self-assemble
into planar nanostructures in which the helical peptides are
2
0,25
arranged parallel to the 2D planes.
To investigate the self-
assembled structures of the peptides in aqueous solution including
KF, we performed transmission electron microscopy (TEM)
experiments. At room temperature, we could not observe any
noticeable aggregates, which was additionally confirmed by
dynamic light scattering (DLS) measurements, indicating that
both the peptides exist as molecularly dissolved states at room
temperature. Upon heating, however, the peptides self-assemble
into flat membrane structures. The TEM images of peptide 2
showed flat disks with an average diameter of ~80 nm (Figure 3a).
Notably, the disk plane has a directionally folded edge, implying
that the thermally-induced peptide helices are aligned in a one
direction parallel to the disk planes (Figure 3d). The formation of
the flat nanostructures was also confirmed using cryo-TEM with
the vitrified solution, which provides further evidence that the
aggregates exist as flat disks in bulk solution (Figure 3b and Fig-
o
to 50 C, however, the strong minimum is apparently red-shifted
to 208 nm together with the appearance of another minimum at
2
22 nm, demonstrating that the random coil conformation of the
2
2
peptide transforms into an α-helical structure. Similarly, peptide
3 based on three dendrons as side chains exhibits a strong nega-
tive band at 196 nm at room temperature, demonstrating the pep-
tide is mostly in a random coil conformation. At higher tempera-
ture, however, the CD spectrum shows two negative bands at 206
nm and 222 nm, indicating that the peptide is predominantly in an
α-helical conformation. It should be noted that the CD intensity at
2
22 nm of peptide 3 is stronger than that of peptide 2, suggestive
of a higher content of α-helical conformation than that of peptide
. The results demonstrate that both peptides 2 and 3 undergo
2
conformational switching from random coil to α-helix upon heat-
ing. This is attributed to thermal dehydration of the oligoether
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Journal of the American Chemical Society
ure S6). Additional structural information of the disks was ob-
flat membranes along two orthogonal directions of the fiber axis
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tained by atomic force microscopy (AFM) measurements on hy-
drophilic mica substrate in the completely dried state (Figure 3c).
The AFM image of the peptide revealed flat disks with a thickness
of 3.2 nm, which is in reasonable agreement with the expected
thickness of roughly single layer packing (Figure 3d). In addition
to this example, protein-lipopeptide complexes and metal-
coordinated oligopeptides have been reported to form flat nano-
and of the helical peptide axis, respectively. Considering that
peptide 2 with less α-helical content self-assembles into flat disks,
the higher α-helical content in peptide 3 plays a key role in the
formation of curved vesicles through the lateral association of pre-
formed ribbons.
Considering that the vesicular walls consist of the parallel
arrangements of rod-like α-helical peptides to the wall plane, the
void spaces formed between the helical peptide arrangements
26
disks.
27
Unlike peptide 2 which forms flat nanostructures, peptide 3
based on three dendron side groups self-assembles into curved
vesicular structures, as evidenced by TEM, scanning electron
microscopy (SEM), and DLS measurements (Figure 4). When
would be chiral. Accordingly, we envisioned that the vesicular
walls function as an enantioselective membrane as the one
enantiomer over the other one preferentially passes through across
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the membrane. To corroborate the enantioselective permeability
of the vesicular walls, we added racemic 1-(4-bromophenyl)
ethanol (5 mM) to a solution of peptide 3 at room temperature
o
heated to 50 C at which the conformation of the peptide changes
into α-helix, the TEM image stained with uranyl acetate revealed
the formation of spherical objects with diameters ranging from 60
nm to 120 nm. These results indicate that the induced helical con-
formation triggers the formation of the self-assembled structures.
Cryo-TEM investigations confirmed the presence of spherical
aggregates with a dark outer circle expected from the 2-D projec-
tion of hollow vesicles with a uniform thickness of 3.2 nm. This
was further confirmed by X-ray diffraction (XRD) experiments
which showed the d value of 3.0 nm (Figure S7). DLS measure-
ments revealed that the aggregates have an average diameter of
o
(Figure 5). Upon heating the solution to 55 C, the peptide
molecules self-assemble into hollow vesicles with simultaneous
capture of the racemate within their hollow interiors. The
encapsulation of the racemate within the vesicular interior was
confirmed by tracing high-performance liquid chromatography
HPLC after separation of the free racemate from the vesicular
solution using a Sephadex column (Figure S9). The preferential
release of the encapsulated enantiomers was then monitored by
tracing HPLC as a function of release time after separation of the
vesicles using a Sephadex column. The permeation through the
vesicular walls is enantioselective as shown in Figure 5a in which
the concentrations of both encapsulated enantiomers decrease
with increasing permeation time. Notably, the (R)-enantiomer
diffuses out faster than the (S)-enantiomer. After 3 hr separation,
the enantioselectivity appears to be maximum and the
enantiomeric excess (ee, given in %) reaches 12 %. This result
demonstrates that the racemic molecule is encapsulated inside the
vesicular interior through the spontaneous formation of vesicular
walls and then release out (R)-enantiomer selectively. The
preferential diffusion of the enantiomer indicates that the
vesicular walls allow a chiral environment for the racemate which
is attributed to the lateral arrangements of the short helical
peptides.
~
90 nm, which is in reasonable agreement with the size observed
by TEM. Considering the calculated molecular dimensions, the
peptide helices are arranged parallel to the wall of the vesicle with
hydrophilic oligoether side chains exposed to the water environ-
ment. The formation of the nanostructures at higher temperatures
was further confirmed using SEM, which provides additional
evidence that the aggregates exist as spherical objects (Figure 4c).
Figure 4. (a) TEM and Cryo-TEM (inset) images of peptide 3 in 5
o
mM aqueous KF solution at 50 C. (b) DLS of peptide 3 in 5 mM
o
aqueous KF solution at 50 C. (c) SEM image of peptide 3 in 5
o
mM aqueous KF solution at 50 C. (d) Schematic representation
of the formation of vesicular assembly of peptide 3.
To gain insight into the formation of the hollow spherical struc-
ture, we performed TEM experiments with a highly diluted condi-
tion (0.002 wt%) of peptide 3 (Figure S8). In contrast to peptide 2
with a lack of any noticeable aggregates at the identical condition,
the image of peptide 3 showed short nanofibers with a uniform
diameter of 3.8 nm, demonstrating that the vesicular walls consist
of the lateral association of the elementary nanofibers. Consider-
ing the calculated length of the peptide helix (3.5 nm), the nano-
fibers consist of a ribbon-like lateral association of the peptide
helices with dendrimer chains located at both faces of the ribbons.
With increasing concentration, however, the elementary nano-
fibers further assemble through side by side interactions to gener-
ate a flat membrane structure (Figure 4d). This result implies that
the vesicular structure of peptide 3 originates from folding of the
Figure 5. (a) Schematic representation of encapsulation and chiral
separation of racemic 1-(4-bromophenyl)ethanol with peptide 3.
(
b) Enantioselective permeation of racemic 1-(4-bromophenyl)
ethanol through chiral membrane assembly of peptide 3. (c)
HPLC chromatograms of racemic 1-(4-bromophenyl)ethanol with
various time.
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The results described herein demonstrate that the lateral
incorporation of oligoether side groups into a short peptide
backbone provides an efficient strategy to allow the short peptides
to undergo conformational switching from random coils to α-
helices (Figure 1). The switching feature of the peptide
conformation is attributed to reversible shielding of the peptide
backbone from water environment by the oligoether dendron side
groups. Furthermore, the switchable α-helical peptides self-
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like α-helices are aligned parallel to each other. Peptide 2 based
on two oligoether dendrons forms discrete disks while peptide 3
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responsible for the formation of the switchable peptide
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conformation. Importantly, the hollow vesicles formed from
peptide 3 can spontaneously capture a racemic mixture through
the self-formation of membrane walls upon heating and
enantioselectively release the guest molecules through preferential
diffusion across the vesicular walls. Considering that most of the
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membrane nanostructures are far from controlled encapsulation,
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(
ASSOCIATED CONTENT
Supporting Information
(
(
Experimental procedures, synthesis of peptides, MALDI-TOF
data, HPLC data, XRD data, NMR data, and TEM image. This
material is available free of charge via the Internet at
http://pubs.acs.org.
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AUTHOR INFORMATION
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Corresponding Author
mslee@jlu.edu.cn, yjkim@jlu.edu.cn
Notes
The authors declare no competing financial interests.
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ACKNOWLEDGMENT
This work was supported by 1000 Program, NSFC (Grant
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