Templated hierarchical self-assembly of poly(p-aryltriazole) foldamers

Article abstract of DOI:10.1002/anie.201303135

A biomimetic approach has been used for the templated self-assembly of a helical poly(para-aryltriazole) foldamer. The solvophobic folding process yields helices that further self-assemble into long nanotubes (see picture; scale bar: 100a nm). Constructs of controlled length and chirality can be generated by applying a poly(γ-benzyl-l-glutamate) scaffold at the appropriate assembly conditions, mimicking tobacco mosaic virus self-assembly. Copyright

Full text of DOI:10.1002/anie.201303135

.
Angewandte
Communications
DOI: 10.1002/anie.201303135
Finite Nanostructures
Templated Hierarchical Self-Assembly of Poly(p-aryltriazole)
Foldamers**
Rueben Pfukwa, Paul H. J. Kouwer, Alan E. Rowan,* and Bert Klumperman*
Dynamic equilibrium conditions in biological self-assembly
In our poly(para-aryltriazole) [P(p-AT)] system, a cres-
[1]
lead to efficient information transfer and self-regulation. To
implement equilibrium self-assembly, and create large finite
nanostructures, there is a need to utilize building blocks with
well-characterized and predictable conformational behavior.
Foldamers are ideal models for understanding the folding and
hierarchical self-assembly of biopolymers, owing to the
predictability of their folding behavior and the relative ease
cent shape is induced by adopting a 1,4-disubstitution pattern
of the triazole ring. In combination with an extended cisoid
conformation (Scheme 1a) the crescent shape enforces hel-
ical folding in P(p-AT)s with a sufficiently large degree of
[2]
of their synthesis. A popular design of synthetic foldamers is
based on aromatic rings, joined by rigid linking groups such as
[
3]
[2d,4]
[5]
[6]
acetylenes, amides,
ureas, and triazoles. More recent
research on these “aryl-rigid linker” foldamer systems is
directed at forming more advanced architectures than mere
[
7]
helices and at the introduction of functionality. For these
systems, however, a full description of the conformational
intermediates between the unfolded and fully folded con-
formations is often still lacking. The characterization of the
intermediates involved in the folding process allows for
increased understanding and, more importantly, gives the
opportunity to control and manipulate the self-assembly
process more precisely. Herein, we describe a new helicity
codon based on a para-linked aryltriazole system, where we
are able to fully characterize the conformational transition
processes. We show that the intermediate conformations are
the ideal starting point for controlled hierarchical assembly
and we demonstrate this concept by using macromolecular
templating in the construction of well-defined assemblies of
[
8]
finite dimensions and helicity, much like the controlled
assembly of tobacco mosaic virus (TMV).
[9]
Scheme 1. a) Helicity codon, b) calculated helix, and c) P(p-AT) general
structure.
[
*] Dr. R. Pfukwa, Prof. B. Klumperman
Stellenbosch University
Department of Chemistry and Polymer Science
Private Bag X1, Matieland 7602 (South Africa)
E-mail: bklump@sun.ac.za
polymerization. Molecular modeling predicted a helical con-
formation with 14.5 repeat units per turn, and a large internal
diameter of approximately 30.6 ꢀ (Scheme 1b). In the
helically folded conformation, each aryl ring has a triazole
ring stacked above and below it. The distance between turns is
approximately 3.8 ꢀ, which is consistent with the turns of the
helix being near van der Waals contact. The large cavity of
the helix is a direct consequence of linking the aryltriazole
units, exclusively, in a para geometry on the benzene ring.
This reduces the curvature of the backbone and many repeat
Homepage: http://www.klumperman-group.net/
Dr. P. H. J. Kouwer, Prof. A. E. Rowan
[10]
Institute of Molecular Materials, Radboud University Nijmegen
Heyendaalseweg135, 6525 AJ, Nijmegen (The Netherlands)
E-mail: a.rowan@science.ru.nl
[
**] This work was supported by the South African Research Chairs
Initiative (SARChI) from the Department of Science and Technology
units are required to complete one turn. The aryltriazole
(
DST), the National Research Foundation (NRF), the Council for the
[2c,11]
linkage has been shown to adopt a flat conformation,
and
Chemical Sciences of the Netherlands Organisation for Scientific
Research, and the EU (ITN Hierarchy, contract PITN-2007-215851).
R.P. thanks the Marie Curie Fellowship for financial support. We
thank Rinske Knoop for the TEM and cryoTEM images, and
Franscious Cummings for the TEM images.
thus when it folds, the torsion is spread over many aryltriazole
links as illustrated by the extensive inter-ring co-planarity
(Scheme 1b).
P(p-AT)s S-1, R-1, and 2 (Scheme 1c) with oligo(ethylene
glycol) substituents were designed to switch conformations in
different solvent environments (for the synthesis, see the
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201303135.
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[
6a,12]
Supporting Information, Scheme S1).
Enantiopure chiral
conformation. In the transition regime, however, the polymer,
side chains were installed on P(p-AT)s S-1 and R-1 to direct
which shows the positive Cotton effect, is not as well defined
and we describe its conformation as a “loose spring”
(Scheme 2). As the two conformations are spectroscopically
[13]
the screw-sense of the helical assemblies.
available techniques to study folding behavior,
Of the many
[
13a,14]
we used
UV/Vis and CD spectroscopy to track solvent dependent
conformational changes and to identify intermediate struc-
tures of the folding process.
Spectroscopic signatures of folding were determined from
solutions of P(p-AT) S-1 in DMF/water (non-selective/
selective solvent, respectively). The random coil, which
prevails in DMF, is characterized by a UV peak at 284 nm
and a shoulder at 310 nm, and is CD silent (red spectra,
Figure 1a). From 10% v/v water in DMF (10% H O), the
2
Scheme 2. Solvent-dependent hierarchical self-assembly pathway of
P(p-AT)s, illustrating the key conformational structures. The color code
is linked to the colors in Figure 1.
clearly resolved, we deconvoluted the UV spectra and
obtained a profile of the equilibrium conformational popu-
lations as a function of solvent composition (Figure 1b). The
analysis shows that at low water content, random coil and
“
loose spring” conformations are in equilibrium; at inter-
mediate water content, “loose springs” and stable helices are
in equilibrium. In fact, we do not observe a region where
random coils and stable helices coexist. The inflection point,
at 13% water, marks the coil-to-helix transition midpoint
with the loose spring as the dominant conformation. Spec-
troscopic resolution of intermediate conformers is unprece-
dented for amphiphilic “aryl-rigid linker” foldamers. We
expect this conformation to be very dynamic and also
sensitive towards changes in its environment, which makes
it the ideal starting point for further hierarchical assembly
processes. The increase in amplitude of the CD couplet and
the red-shifts of the isodichroic point and the UV band at
310 nm between 20–28% water is explained as a further
tightening of the stable helical conformation.
Figure 1. a) UV (bottom) and CD spectra (top) of the solvent titrations
of P(p-AT)-S-1; b) plots of the UV absorbance ratio (A310/A284) (top)
and equilibrium populations of various conformational species
(
bottom) as a function of solvent composition.
shoulder peak at about 310 nm increases in intensity whilst
the peak at 284 nm decreases (orange UV spectra, Figure 1a),
and at 13% H O, the peaks at 284 and 310 nm have equal
2
intensities. With further increments of water the peak at
3
10 nm increases and red shifts, whilst the peak at 284 nm
attenuates. The plot of the ratio of the UV bands at 310 nm
and 284 nm (A310/A284), as a function of solvent composi-
Beyond 28% H O, the UV analysis shows an upswing in
2
[3a]
tion reveals two distinct regimes (Figure 1b). From 0% to
the A310/A284 plot whereas the CD signal decreases, owing to
[16]
about 25% H O (black dots), the plot is sigmoidal, a charac-
kinetic trapping
(Figure 1a,b, top, respectively). This
2
[14d,15]
teristic of cooperative conformational transitions.
After
suggests that at high water content, the intramolecular
structure of the helices stays intact, but that the molecules
now start assembling into a tertiary structure, that is, nano-
the plateau from about 28% H O onwards, the ratio steadily
2
increases again, leveling off at high water fractions.
[17]
In the CD spectra, a single positive Cotton effect appears
tubes. TEM and cryoTEM analyses of P(p-AT) S-1 show
convincing evidence for the formation of helical columns,
formed by stacked helices, which further aggregate into
bundles and coils (Figure 2a,b).
at 10% H O (orange spectra), growing in intensity with
2
increasing water content. At about 20% H O, the Cotton
2
effect, however, evolved into a bisignate signal exhibiting
negative exciton chirality, with an isodichroic point at 330 nm
suggesting the formation of a helical conformation with
preferred handedness owing to chirality transfer from the side
The UV and CD spectra of P(p-AT)s R-1 and 2 as
a function of solvent composition evolve analogously to P(p-
AT) S-1 (Supporting Information, Figures S8 and S9), indi-
cating that they follow the same hierarchical pathway. As
expected, the Cotton effects of P(p-AT)s S-1 and R-1 are
exact mirror images (Supporting Information, Figure S8E),
which demonstrates that these helical foldamers have pre-
ferred, and opposite, twist sense biases imparted by their
[
13]
chain to the backbone (green spectra). From 20% H O, the
2
amplitude of the Cotton effect further increases with increas-
ing H O content, peaking at 28% H O. The isodichroic point
2
2
shifts to 325 nm. Upon further increase of the water fraction
beyond 28% H O the amplitude of the Cotton effect
2
[16]
[13]
decreases, but the isodichroic point does not change (blue
spectra).
chiral side chains. The longer oEG side chain in P(p-AT) 2
gives rise to an increased solubility in water and thus slightly
weaker solvophobic interactions. This shifts the coil-to-helix
The formation of a single clear bisignate Cotton effect at
2
0% H O indicates that the coil-to-helix transition is
transition midpoint to 19% H O and the formation of higher-
2
2
completed and the polymer is in a well-defined helical
order structures starts at about 40% H O (Supporting
2
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Scheme 3. Proposed diastereoselective templated self-assembly of P(p-
AT) 2.
poly(g-benzyl-l-glutamate) (PBLG) a-helix as our RNA
[
18]
mimic. The stiff polymer has a diameter of about 1.6 nm,
[
19]
which matches well with the calculated helical cavity, and
its hydrophobic nature is expected to drive the assembly. As
the starting point we investigated the influence of the
template at the coil-to-helix transition midpoint, which for
P(p-AT) 2 is 18% H O (Scheme 3).
2
Evidence for chiral information transfer between the
achiral P(p-AT) 2 and the chiral PBLG was obtained by CD
spectroscopy (Figure 3a). A negative bisignate Cotton effect
is observed in the wavelength region where only the P(p-AT)
Figure 2. a) TEM image of P(p-AT) S-1 [1.11 mm], prepared from 80%
H O; b) CryoTEM image of P(p-AT) 2 [29.8 mm] prepared from 100%
2
2
absorbs, which points to an enantiomeric excess of one of
H O. The irregular shaped blots (some are circled) are ice crystals
2
both helices as a result of macromolecular templating. Two
control experiments, either with P(p-AT) 2 in the random-coil
contaminating the surface of the sample; c) the self-assembled com-
plex of P(p-AT) 2 with PBLG B, which shows nanostructures with
lengths of 62.8Æ9.1 nm.
conformation (0% H O) or without the template present,
2
showed no chiral expression of the foldamer (Figure 3a).
Information,
Cryo-TEM
Figure S9).
experiments
using the achiral P(p-AT) 2
at high water content con-
firm the formation of solu-
tion stable tertiary structures
(
Figure 2b;
Supporting
Figure S12).
Information,
The helices stack into long
columns of varying lengths.
The assembly process
thus far follows classical
hierarchical foldamer organ-
ization where stack forma-
tion and length are thermo-
[6d,17]
dynamically controlled.
To direct this assembly pro-
cess to yield well-defined
structures, we used a poly-
mer template. This approach
is inspired by nature, which
applies it in the self-assem-
bly of, for instance, the
tobacco
mosaic
virus
(
TMV). TMV is an asym-
metric rod-shaped virus
comprised of protein capsids
Figure 3. a) CD spectra of P(p-AT) 2 and PBLG B in 100% DMF (c) and in 18% H O (a), and P(p-AT) 2
2
alone in 18% H O (g); B) Job plot of P(p-AT) 2 and PBLG A-C (* A, ^ B, * C) to determine the
2
encasing
a
single RNA
stoichiometry of the inclusion complex (inset: plot of stoichiometric ratio versus template length: black=
theoretical, red=experimental); c) plot of CD activity at 333 nm versus solvent composition for the
stoichiometric complex of P(p-AT) 2 and PBLG B (* “quick”, * “slow” water addition); d) evolution of CD
spectra with increasing template concentration for inclusion complex P(p-AT) S-1 and PBLG B (orange
strand that regulates the
length and chirality of the
[9b]
virus complex.
We chose
the rigid and hydrophobic curve=P(p-AT) S-1 without PBLG template).
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Length information transfer is demonstrated via a length
dependent templating effect. CD titrations of three PBLG
templates of differing length (PBLG A, B, and C) were
carried out. A subsequent Job plot analysis (Figure 3b)
showed that the stoichiometry of the complexes closely
correspond to what can be expected considering the molec-
ular weights (that is, lengths) of the templates (Supporting
Information, Table S5) and the (modeled) packing distance of
60 nm) present showed well-defined nanostructures of match-
ing length, 62.8 Æ 9.1 nm (Figure 2c).
In conclusion, we presented a new TMV mimic composed
of 1,4-aryl-disubstituted-1,2,3-triazoles foldamers and a-hel-
ical PBLG templates. Assembly studies in the absence of the
template revealed the intermediate conformations between
a random coil and hierarchically built-up (helical) bundles. In
fact, full spectroscopic resolution allowed us to profile the
populations of the intermediates. The template then transfers
both chiral and dimensional information onto the foldamer, in
the process changing the thermodynamics of the foldamer
assembly process. Our studies clearly show that the informa-
tion transfer is most effective right at the coil-to-helix
transition midpoint. Current on-going studies are focused
on understanding the kinetics of the templated self-assembly.
the stable helix. Indeed, the linear increase of the average
P(p-AT)2
number of foldamers N
with the length of the template
shows a direct analogy to the length-dependent templating
effect of TMV.
The hypothesis that templating is most effective from the
coil-to-helix transition midpoint of the foldamers was tested
by measuring the CD signals of stoichiometric complexes
prepared at various volume fractions of water (Figure 3c).
Below 10% water, no CD signal is observed as the foldamer is
unfolded. The highest CD signals are observed from 18-20%
water in DMF, around the coil-to-helix transition midpoint of
the foldamer, where P(p-AT) 2 forms a racemic mixture of
left and right handed “loose springs”. The template then
interacts more favorably with the foldamer helix with
a matching screw sense, which biases the system towards the
chiral complex (Scheme 3). Above 25% water, however,
depending on the rate of addition of the selective solvent
Received: April 15, 2013
Revised: July 23, 2013
Published online: September 3, 2013
Keywords: biomimetic synthesis · foldamers ·
.
information transfer · self-assembly · template
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Supporting Information.
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