PH-regulated selectivity in supramolecular polymerizations: Switching between co- And homopolymers

Article abstract of DOI:10.1002/chem.201406281

A strategy is presented to regulate the selectivity in aqueous supramolecular polymerizations by changes in pH. In neutral buffered conditions, oppositely charged phe-nylalanine-based dendritic peptide amphiphiles self-assemble into (A-B)_n alternating copolymers of low polydispersity when mixed in a 1:1 comonomer feed ratio. Via pH switch of the glutamic acid and lysine side chains, attractive Coulomb interactions in the coassembled materials are screened and selective polymerization occurs to form (A)_n homopolymers of the acidic comonomer at low pH and (B)_n homopolymers of the basic comonomer at high pH, while the complementary comonomer is released during the transition. Reversible switching is demonstrated between these three different polymeric states, which were characterized by CD and fluorescence spectroscopy, using a peptide based minimalistic fluorophore/quencher pair, and transmission electron microscopy.

Full text of DOI:10.1002/chem.201406281

DOI: 10.1002/chem.201406281
Full Paper
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Supramolecular Polymers
pH-Regulated Selectivity in Supramolecular Polymerizations:
Switching between Co- and Homopolymers
Hendrik Frisch,[a] Yan Nie,[b] Stefan Raunser,[b] and Pol Besenius*[a]
Abstract: A strategy is presented to regulate the selectivity
in aqueous supramolecular polymerizations by changes in
pH. In neutral buffered conditions, oppositely charged phe-
nylalanine-based dendritic peptide amphiphiles self-assem-
ble into (AÀB)n alternating copolymers of low polydispersity
when mixed in a 1:1 comonomer feed ratio. Via pH switch
of the glutamic acid and lysine side chains, attractive Cou-
lomb interactions in the coassembled materials are screened
and selective polymerization occurs to form (A)n homopoly-
mers of the acidic comonomer at low pH and (B)n homopol-
ymers of the basic comonomer at high pH, while the com-
plementary comonomer is released during the transition. Re-
versible switching is demonstrated between these three dif-
ferent polymeric states, which were characterized by CD and
fluorescence spectroscopy, using a peptide based minimalis-
tic fluorophore/quencher pair, and transmission electron mi-
croscopy.
Introduction
design a covalent or supramolecular polymerization strategy,
whereby the polymer composition can be switched reversibly
between two or more states by an external trigger.[9]
Proteins and nucleic acids are two classes of key polymeric bio-
molecules that are produced by living organisms. In the case
of proteins, their specific amino acid sequence is encoded to
guide their folding into a variety of functional biopolymers.
This precisely defined arrangement of monomeric building
blocks into complex 3D assemblies has inspired chemists to in-
vestigate synthetic polymerizations of controlled monomer se-
quences.[1] Most approaches are kinetically controlled,[1b,2] use
template approaches,[3] and chain-shuttling mechanisms to
yield periodic patterns,[4] or block copolymer architectures.[5]
Compared to covalent polymer synthesis,[1] there are few ex-
amples that enable control over sequence specificity, monomer
incorporation, or block polymer morphologies by using supra-
molecular chemistry:[6] Winnik, Manners, and co-workers pio-
neered kinetic control in the self-assembly of block copolymers
with crystallizable cores yielding fiber-like micelles with tunable
length, multiblock structure, and very low polydispersity;[7] Sij-
besma and co-workers reported self-sorting in bisurea-based
rod-like micelles in water, whereby a mixture of different mon-
omers selectively assemble into homopolymeric rod-like aggre-
gates.[8] To our knowledge, no attempts have been made to
In a complementary approach to the self-assembly of pH-
switchable small zwitterions,[10] or coiled-coil peptide motifs
that are stabilized by electrostatic interactions,[11] and the
larger body of work on b-sheet encoded peptides,[12] we re-
cently reported ampholytic supramolecular copolymers.[13] In
these self-assembled rod-like materials, complementary sites of
interaction (i.e., pairs of acid/base groups) are embedded into
the pentapeptide-sequenced dendritic comonomers via alter-
nating hydrophobic/hydrophilic amino acids. Based on this
design principle, we hereby demonstrate an approach to regu-
late the selectivity in supramolecular polymerizations by pH. In
neutral buffer, phenylalanine–lysine (FK)- and phenylalanine–
glutamic acid (FE)-based dendritic amphiphilic peptides 1 and
2 self-assemble into well-defined 1À2 copolymers (Figure 1).
By switching off the negative or positive charges on the oppo-
sitely charged comonomers by modulation of the pH,[14] selec-
tive homopolymerization occurs with the simultaneous release
of the complementary comonomer. This is the first report of
a supramolecular polymerization in solution that can be
switched reversibly between three different composition
states: homopolymers of 1, 1À2 copolymers, and homopoly-
mers of 2.
[a] H. Frisch, Dr. P. Besenius
Organic Chemistry Institute and CeNTech
Westfꢀlische Wilhelms-Universitꢀt Mꢁnster
Corrensstrasse 40, 48149 Mꢁnster (Germany)
E-mail: p.besenius@uni-muenster.de
Results and Discussion
Using a convergent synthetic approach, we incorporated very
hydrophobic FE- and FK-based alternating amino acid sequen-
ces in each of side arms of the C3-symmetrical comonomers
1 and 2, as well as an apolar hexyl spacer coupled to a hydro-
philic tetraethylene glycol peripheral dendron (Figure 1). The
latter considerably improved the solubility of the building
[b] Dr. Y. Nie, Prof. Dr. S. Raunser
Department of Structural Biochemistry
Max Planck Institute of Molecular Physiology
Otto-Hahn-Strasse 11, 44227 Dortmund (Germany)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201406281.
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1:1 mixture of 1 and 2 is de-
creased to pH<4, the emission
band increases to the intensity
of the isolated solution of 1. Due
to protonation of the glutamic
acid based monomer, the 1À2
copolymer falls apart because of
a loss of the attractive Coulomb
interactions in the oppositely
charged side chains. Monomer
1 is thereby released and its
photoluminescent properties re-
stored. Intriguingly, by raising
the pH of a coassembled materi-
al of 1 and 2 from pH 7.4 to
pH>10, the emission drops by
a
further 20% to about the
same value observed in the iso-
lated solution of 1 (Figure 2A
and Figure S2 in the Supporting
Information). The homopolymeri-
zation of the free amine deriva-
tive of 1 is thereby not influ-
enced by the presence of 2 in
solution. Remarkably, the three
different polymeric states can be
reversibly switched by repeated
pH cycling (Figure 2B and Fig-
ure S3 in the Supporting Infor-
mation). We postulate the differ-
ent states to be homopolymers
of 1 (pH>10), copolymers of 1À
Figure 1. A) Chemical structures of the C3-symmetric dendritic peptide comonomers 1 and 2; B) their pH-regulat-
ed supramolecular polymerization into homopolymers of 1 and 2, at high and low pH respectively, and 1À2 co-
polymers at neutral pH.
blocks. Finally, we also incorporated the fluorophore p-cyano-
phenylalanine (Cnf) and the thioamide analogue of alanine
(Ala’) on the FK- and FE-based comonomers, respectively. The
aim was to investigate the supramolecular polymerization by
fluorescence spectroscopy and resonance energy transfer
(RET), a powerful tool to study distance-dependent events,
such as conformational changes in proteins. The Cnf–thioa-
mide couple was coined as a minimalistic fluorophore/quench-
er pair by Petersson and co-workers and has a working dis-
tance of 0.8–3.0 nm, which is well-suited for our copolymers.[15]
Photoluminescence spectroscopy experiments containing
only the fluorescent monomer 1 show a sharp 50% decrease
in the emission intensity at pH>9.5 (Figure 2A and Figure S1
in the Supporting Information). This is a first indication that,
due to the deprotonation of the lysine side chains, the core of
the dendritic peptide becomes more hydrophobic and self-as-
sembly into homopolymers occurs, which quenches the fluo-
rescence of the Cnf moiety. In addition, the presence of free
amines has been reported to quench the Cnf emission.[16] If, at
neutral pH, the complementary comonomer 2 is added in
a 1:1 feed ratio to a solution of 1, the fluorescence intensity
drops by 35% (Figure 2A and Figure S2 in the Supporting In-
formation). This is strong evidence that supramolecular 1À2
copolymers are formed, which leads to a RET-promoted de-
crease in the observed fluorescence intensity. If the pH of the
2 (neutral pH), and homopolymers of 2 (pH<4).
To correlate the spectroscopic findings with morphological
investigations, negative-stain transmission electron microscopy
(TEM) experiments were performed. After depositing a solution
of either comonomer at pH 7.4, small isotropic objects of 9 nm
for solutions of 1 (see the Supporting Information, Fig-
ure S4A,B) and 7 nm for solutions of 2 (see the Supporting In-
formation, Figure S6A,B) were obtained. This confirms that, at
neutral pH, the 6 cationic charges in monomer 1 and 6 anionic
charges in monomer 2 prevent the formation of supramolec-
ular homopolymers due to electrostatic repulsive interactions.
However, by raising the pH of the solution containing the
basic monomer 1 to pH 11, anisotropic nanorod-like structures
were obtained with a number-average length Ln =38 nm and
a thickness of 11 nm (see the Supporting Information, Figur-
es S4C,D and S5). The thickness of the rods is in good agree-
ment with the diameter of the molecular building blocks,
which corresponds to an estimated 7.2 nm for the extended
hydrophobic core and 12.5 nm including the stretched out hy-
drophilic dendron. In contrast, decreasing the pH of a solution
of the acidic monomer 2 led to very long rods with an abso-
lute length that could not be determined accurately (>1 mm;
see the Supporting Information, Figure S6C,D). Remarkably, we
were able to resolve a left-handed helical secondary structure
in these rods, which show thicknesses ranging from 6.9 nm to
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Figure 2. A) pH-dependent fluorescence emission intensity (lem =295 nm,
lexc =240 nm) of the fluorescent monomer 1 alone (6 mm, shown as purple
squares), and a 1:1 mixture of 1 (6 mm) and the quenching monomer 2
(6 mm) in 5 mm phosphate buffer (shown as purple/yellow diamonds);
B) pH-dependent fluorescence intensity after repeated addition of NaOH
and HCl.
10.4 nm depending on their orientation in the field of view
(see the Supporting Information, Figures S7, S8, and S11A).
Crucially, when both comonomers were premixed in a 1:1
ratio at pH 7.4, well-defined anisotropic structures exhibiting
right-handed helical arrangement were observed with
a number average rod-length Ln =56 nm and a polydispersity
index (PDI) Lw/Ln =1.3 (Figure 3, 4B, S9A–B and S11B).[7] Their
thicknesses ranged from 6.4 nm to 10.4 nm (see the Support-
ing Information, Figure S10), and were in good agreement
with the diameter of the molecular building blocks. The poly-
dispersity for the contour length distribution of the rod-like co-
polymers was very narrow. While this could not be directly
compared to the molecular weight distribution of supramolec-
ular polymers, it is known that such a narrow distribution can
only be obtained in a non-cooperative process. The copoly-
Figure 3. A) TEM image of the copolymer of 1 and 2 at pH 7.4; individual co-
polymers measured for length histogram are marked with red lines (scale
bar=100 nm); B) length histogram of the rod-like copolymer: Ln =56 nm,
Lw =70 nm, s=28 nm, Lw/Ln =1.3, s/Ln =0.5, n=218. (Values of Ln and Lw
were calculated as previously reported[7]); C) all class averages of the copoly-
mer of 1 and 2 at pH 7.4 (scale bar=10 nm).
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Figure 4. TEM images: A) The homopolymer of 2—monomer 1 mixture at pH 2.0; B) the 1À2 copolymer at pH 7.4; C) the homopolymer of 1—monomer 2
mixture at pH 11.0 (scale bars=100 nm).
mers therefore behaved like step-growth polymers.[6] Van der
Schoot and Jabbari-Farouji recently disclosed a theoretical
model for supramolecular copolymerizations in two-compo-
nent systems.[17] In line with their predictions for a non-cooper-
ative mechanism based on two comonomers that have no
driving force for homopolymerization, we postulate that the
copolymers have a strictly alternating 1À2 monomer sequence
in the copolymers.
tion occurred at pH 3.8 (see the Supporting Information, Fig-
ure S14), whereas for the basic FK-based monomer, the transi-
tion occurred at pH 10.5 (see the Supporting Information, Fig-
ure S13). Both values are in good agreement with their expect-
ed pKa values. The CD spectrum obtained upon mixing an
equimolar solution of 1 and 2 at neutral pH deviates strongly
from the linear combination of the two isolated solutions of
both comonomers at the same pH (see the Supporting Infor-
mation, Figure S12D). If the pH of the same solution of the 1À
2 hetero-copolymers is adjusted to either pH 12 or pH 2, the
CD spectra obtained are identical to the linear combination of
the measured solutions for the homopolymer of 2 and mono-
mer 1, or homopolymer of 1 and monomer 2 (see the Support-
ing Information, Figure S12C,E). This is in full agreement with
the interpretation of fluorescence spectroscopic data and TEM
micrographs. When switching off the copolymerization of
1 and 2 at high and low pH, we follow the characteristic CD
signals for the copolymers; the sharp transitions at pH 3.8 and
pH 10.5 overlap with the monomer-homopolymer transitions
observed for the isolated solutions of 1 and 2 (Figure 5A and
Figures S15 and S16 in the Supporting Information). Upon pH
switching, the 1À2 copolymers fall apart, and self-assembly
into the respective homopolymers takes place while the com-
plementary comonomer is released from the copolymers.
After acidifying a solution of the copolymers to pH 2, we ob-
served homopolymers of 2 as micrometer long nanorods and
monomers of 1 as <10 nm-sized spherical objects (Figure 4A
and Figure S9C,D in the Supporting Information). When the
pH was increased from pH 7.4 to pH 11, homopolymers of
1 were obtained as short nanorods in the presence of mono-
mers of 2 as nanosized spheres (Figure 4C and Figure S9E,F in
the Supporting Information). Together with the photolumines-
cence studies, these findings confirm that, under neutral condi-
tions, supramolecular polymerization into well-defined copoly-
mers of 1 and 2 occurs. Note the elegance of our approach; re-
pulsive Coulomb interactions between monomers of the same
charge prevent their assembly into homopolymers. However,
attractive Coulomb interactions in the oppositely charged co-
monomers reinforce self-assembly of b-sheet encoded peptide
sequences.[13] Through pH switching of the basic and acidic
peptide monomers, attractive electrostatic interactions in the
copolymers are screened, and selective homopolymerization of
1 (high pH) or 2 (low pH) occurs due to the hydrophobic phe-
nylalanine based core, while the complementary comonomer
is released.
To utilize the concept of pH-regulated selectivity in supra-
molecular polymerizations, it would be advantageous if the in-
corporated switches could also be adjusted for a particular ap-
plication. For example, tuning instabilities towards pH and
ionic strength is a highly effective strategy for synthetic gene
delivery vectors, whereby a decrease in pH and osmotic swel-
ling triggers the release of genome material from intracellular
compartments.[18] With this in mind, we investigated the ionic-
strength-dependent copolymer-to-homopolymer transitions; in
the presence of 25 mm NaCl, the pH stability window for the
supramolecular copolymerization narrowed from pH 3.8–
pH 10.5 to pH 4.2–9.5 (Figure 5B and Figures S17 and S18 in
the Supporting Information). As expected, an increase in the
ionic strength screened the attractive Coulomb interactions
To further elucidate the pH-regulated self-assembly into
homo- and hetero-copolymers of 1 and 2, we performed circu-
lar dichroism (CD) spectroscopy experiments. Upon changing
the pH from pH 7.4 to pH 12.0 for 1 and from pH 7.4 to pH 3.2
for 2, significant changes in the CD bands were observed (see
the Supporting Information, Figure S12–S14). Consistent with
the results obtained from TEM experiments, we assign these
changes to a pH-induced monomer to homopolymer transi-
tion. For the acidic FE-based building block, the sharp transi-
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the coassembled materials were lost, and selective polymeri-
zation occurred to form homopolymers of the basic comono-
mer at high pH and homopolymers of the acidic comonomer
at low pH. The transition between the copolymers and either
of the homopolymers narrowed on increasing the ionic
strength. The general nature of the concept could be readily
utilized to fabricate new biomaterials in solution, in the gel
state, or on surfaces.
Experimental Section
The detailed synthetic procedures, material characterization, and
full details about the instrumentation can be found in the Support-
ing Information. Fluorescence spectra were recorded on a FP-6500
(JASCO) using the software Spectra Manager 2.08.04 and processed
with Origin Pro 9.1 G. All spectra were recorded at 258C with mo-
nomer concentrations of 6 mm, each in 5 mm phosphate buffer.
The pH values were adjusted by the addition of aqueous HCl or
NaOH. For all experiments, the excitation wavelength was 240 nm
and emission data was collected from 260 nm to 380 nm using
quartz fluorometer cells with a path length of 1 cm. The excitation
bandwidth was 3 nm and the emission bandwidth was 5 nm, the
scan rate was 500 nmminÀ1, and the data interval was 0.1 nm. CD
spectra were recorded on a J-815 (JASCO) using the software Spec-
tra Manager 2.08.04 and processed with Origin Pro 9.1 G. All spec-
tra were recorded at 208C with a total monomer concentrations of
60 mm in 5 mm phosphate buffer using quartz cells with a path
length of 2 mm. The low monomer concentrations made sure that
the HT signal was lower than 600 V at all times. In the UV/Vis spec-
tra, no evidence for scattering was observed in any of the solu-
tions. The pH values were adjusted by addition of aqueous HCl
and NaOH. All Spectra were corrected by subtraction of the back-
ground (buffer). The associated UV/Vis spectra were recorded on
a U-650 (JASCO), using the software Spectra Manager 2.08.04, di-
rectly after the fluorescence measurement. The data was processed
with Origin Pro 9.1 G. The UV/Vis spectra were collected between
200 nm and 320 nm. The procedure for grid preparation and
image recording for negative-stain EM was as follows: In brief, 4 mL
sample droplets were adsorbed for 1 min on freshly glow-dis-
charged copper grids (Agar scientific; G2400C) covered by a thin,
continuous carbon film. The grids were then negatively stained
with 0.75% uranyl formate (Polysciences) for 1 min before blotting
with filter papers (Whatman no. 4).[19] All images were recorded
with a JEOL JEM-1400 electron microscope equipped with a LaB6
cathode and operated at 120 kV. Digital electron micrographs were
recorded with a 4kꢁ4k CMOS camera F416 (TVIPS) under minimal
dose conditions (15–20 electrons/ꢂ2) at a calibrated magnification
of 67,535ꢁ, resulting a pixel size of 2.32 ꢂ. The lengths of individu-
al rod-like filaments were measured using boxer from EMAN soft-
ware package.[20] The histograms were prepared using StatPlus:mac
LE (AnalystSoft) with Excel 2011 (Microsoft).
Figure 5. A) Normalized CD data for titrations of a 60 mm aqueous solution
containing a 1:1 mixture of comonomers 1 and 2 (mixed-colored data
points, left y axis), and the isolated mixtures of the monomers (single-col-
ored data points, right y axis); Irel =1 is set for the polymerized state as
switched ‘on’ and Irel =0 is set for the polymerized state as switched ‘off’
(see the Supporting Information, Figures S17–S20); B) normalized CD data
for titrations of a 60 mm aqueous solution containing a 1:1 mixture of como-
nomers 1 and 2 at different pH values in phosphate-buffered (5 mm) water,
without NaCl, and with 25 mm added NaCl (based on Figures S17–S20);
Irel =1 is set for the copolymerized state as switched ‘on’ and Irel =0 is set for
the copolymerized state as switched ‘off’.’
between oppositely charged monomers and destabilized the
1À2 copolymers. In contrast, under neutral conditions (pH 7.4),
full disassembly of the copolymers occurred only at a critical
concentration of 200 mm NaCl (see the Supporting Informa-
tion, Figures S19–S21). Furthermore, in contrast to the large
majority of reported supramolecular polymers that are enthal-
py driven,[6] we observed that the 1À2 copolymers could not
be depolymerized simply by increasing the temperature (see
the Supporting Information, Figure S22), suggesting that desol-
vation and entropic effects are very pronounced.
Conclusions
Acknowledgements
In conclusion, we have presented a biomimetic strategy to reg-
ulate the selectivity in supramolecular polymerizations by
modulation of the pH. Attractive Coulomb interactions in op-
positely charged dendritic peptide amphiphiles reinforced
weak noncovalent interactions to form alternating supramolec-
ular copolymers. Upon pH switching of the lysine and glutamic
acid peptidic monomers, attractive electrostatic interactions in
We thank the Fonds der Chemischen Industrie for a Liebig
[P.B.] and a doctoral [H.F.] fellowship, Prof. Dr. Bart Jan Ravoo
for his support, Dr. Christos Gatsogiannis and Julian von der
Ecken for their help, COST Action CM1005 (Supramolecular
Chemistry in Water). This work was supported by the DFG (SFB
858).
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A. L. Boyle, A. Collins, J. Mantell, T. H. Sharp, M. Antognozzi, P. J. Booth,
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2013, 340, 595–599.
Keywords: controlled polymerization · self-assembly · pH
regulation · polymers · supramolecular chemistry
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Received: November 28, 2014
Published online on && &&, 0000
&
&
Chem. Eur. J. 2015, 21, 1 – 7
www.chemeurj.org
6
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Full Paper
FULL PAPER
Switchcraft: A strategy to regulate the
selectivity in aqueous supramolecular
polymerizations is presented. In neutral
buffer, oppositely charged dendritic
peptide amphiphiles selectively self-as-
semble into alternating copolymers. At
high and low pH, the formation of
either the basic or acidic homopolymer
occurs while the complementary co-
monomer is released. The transition be-
tween these three different polymeric
states is fully reversible and can be
switched multiple times.
&
Supramolecular Polymers
H. Frisch, Y. Nie, S. Raunser, P. Besenius*
&& – &&
pH-Regulated Selectivity in
Supramolecular Polymerizations:
Switching between Co- and
Homopolymers
Chem. Eur. J. 2015, 21, 1 – 7
www.chemeurj.org
7
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ