Oligosaccharides Self-Assemble and Show Intrinsic Optical Properties

Article abstract of DOI:10.1021/jacs.8b11882

Self-assembling peptides and oligonucleotides have given rise to synthetic materials with several applications in nanotechnology. Aggregation of synthetic oligosaccharides into well-defined architectures has not been reported even though natural polysacch

Full text of DOI:10.1021/jacs.8b11882

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Article
Oligosaccharides self-assemble and show intrinsic optical properties
Yang Yu, Soeun Gim, Dongyoon Kim, Zohar A. Arnon, Ehud Gazit, Peter H Seeberger, and Martina Delbianco
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b11882 • Publication Date (Web): 04 Mar 2019
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Yang Yu,⊥,§,‡ Soeun Gim,⊥,§,‡ Dongyoon Kim,⊥ Zohar A. Arnon,⊗ Ehud Gazit,⊗,¶ Peter H. Seeberger,⊥,§,
* and Martina Delbianco⊥,*
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⊥
Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, Am Mühlenberg 1, 14476 Pots-
dam, Germany
§
Department of Chemistry and Biochemistry, Arnimallee 22, 14195 Berlin, Germany
⊗ Department of Molecular Microbiology and Biotechnology, George S. Wise Faculty of Life Sciences, Tel Aviv University,
Tel Aviv 6997801, Israel.
¶ Department of Materials Science and Engineering Iby and Aladar Fleischman Faculty of Engineering, Tel Aviv University,
Tel Aviv 6997801, Israel
Supporting Information Placeholder
polydispersity of chain length and modifications. While synthetic
oligosaccharides should be able to self-assemble into tunable
materials, this process has not been observed for structurally-
defined oligosaccharides as access to pure glycans has been chal-
lenging. Chemical synthesis of oligosaccharides provides an
attractive alternative to the modification of natural polysaccha-
rides; however, it was extremely laborious prior to recent advanc-
es in automated synthesis.13 Rapid access to synthetic oligo- and
polysaccharides provided material for systematic structural stud-
ies, showing that synthetic hexasaccharides may adopt defined
shapes in solution.14
ABSTRACT: Self-assembling peptides and oligonucleotides
have given rise to synthetic materials with several applications in
nanotechnology. Aggregation of synthetic oligosaccharides into
well-defined architectures has not been reported even though
natural polysaccharides, such as cellulose and chitin, are key
structural components of biomaterials. Here, we report that six
synthetic oligosaccharides, ranging from dimers to hexamers, self-
assemble into nanostructures of varying morphologies and emit
within the visible spectrum in an excitation-dependent manner.
Well-defined differences in chain length, monomer modification,
and aggregation methods yield glycomaterials with distinct shapes
and properties. The excitation-dependent fluorescence in a broad
range within the visible spectrum illustrates their potential for use
in optical devices and imaging applications. We anticipate that
our systematic approach of studying well-defined synthetic oligo-
saccharides will form the foundation of our understanding of
carbohydrate interactions in nature.
Here, we report that synthetic oligosaccharides self-assemble into
defined structures. The systematic approach confirmed that differ-
ences in chain length and modification yield glycomaterials with
distinct shapes and properties. This finding is particularly im-
portant in the prospective of creating novel carbohydrate materials
with tunable properties. Moreover, these materials exhibit unex-
pected excitation-dependent intrinsic optical properties that can
expand the applications of these materials even further and may
result in new, cheap, and biocompatible optical devices. The
dramatic differences in the aggregates morphologies stress the
importance of a better knowledge of glycan presentation in bio-
logical systems, where carbohydrate-carbohydrate interactions
regulate several cellular processes.15 We suggest that our ap-
proach, based on the study of the interaction of well-defined
synthetic oligosaccharides, could shed light upon the rules that
regulate cellular recognition and uptake.
Simple peptides1 and nucleic acids2 can spontaneously self-
assemble to form defined supramolecular patterns. These supra-
molecular architectures are the essence of modern bionanotech-
nology, with implications in the medical3 and energy1d, 4 fields.
The discovery that peptide dimers (i.e. diphenyl alanine) self-
assemble provided fundamental insights into the progression of
important diseases.5 The main limitation to the use of these sys-
tems is often associated with the modest quantities that can be
produced. In contrast, natural polysaccharides comprise 80% of
biomass, where they serve mainly structural roles.6 These materi-
als, including cellulose7 and chitin,8 have a strong tendency to
aggregate in well-defined architectures with different physical
properties. Chemical modification tunes polysaccharide proper-
Self-assemby. Hexamer 4 (Figure 1A) proved so poorly soluble
in many organic solvents that further chemical manipulations are
impossible, while a similar compound that carries fewer benzyl
ethers (i.e. hexamer 5) encountered fewer solubility and reactivity
issues.14 These differences likely are a consequence of the for-
mation of supramolecular structures due to strong intermolecular
interactions, such as hydrogen bonding, together with π-π interac-
tions of the benzyl ether modification. Exploiting such interac-
tions to drive the self-assembly should give rise to novel oligosac-
charides materials. Three dimers (1-3) as well as one additional
ties9 to serve as biocompatible,6, cheap, and renewable self-
7c
assembling materials for application in nanotechnology,10 optical
components,7b,
drug delivery systems,12 and tissue
11
engineering.8a However, the use of polysaccharide materials is
limited by poor quality control and reproducibility, owing to the
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hexasaccharide (6) were prepared to probe the influence of chain
The effects of assembly conditions on structure were studied in
length, linkage, and modification on self-assembly (Figure 1A).
Supramolecular aggregation was induced by slow dialysis (D) or
fast solvent-switch (S).16 Oligosaccharides dissolved in a dime-
thylacetamide (DMAc)/water mixture and dialyzed against water
aggregated into nanoparticles with diameters of 40-60 nm (Figure
2A-(a-f)). These particles exist in solution as confirmed by Cryo-
SEM of 2-D (Figure S1) and dynamic light scattering (DLS)
measurements (Figure S2). Direct injection of water into a glycan
solution in HFIP (fast solvent switch) results in faster mixing,
higher oligosaccharide concentration and altered self-assembly
behavior (Figure 2A-(g-l)).17 Needle-like structures were found
for 2-S-HFIP (5-10 µm length, 10-50 nm height and 100-500 nm
width, Figure 2A-h and Figure S3) and a spheroidal architecture
(1-2 µm diameter) for the hexamer 5-S-HFIP analogue (Figure
2A-k). These supramolecular structures were stable for one month
at ambient conditions and resisted dilution and sonication (Figure
S4). 1-S-HFIP assembled into a mixture of rods and toroid struc-
tures (Figure 2A-g), while 4-S-DMAc formed clusters of nanopar-
ticles (Figure 2A-j). Differences in oligosaccharide structure such
as linkage and modification patterns fundamentally affect the
material morphology as 3-S-HFIP (Figure 2A-i) and 6-S-DMAc
(Figure 2A-l) aggregated randomly and did not form any ordered
supramolecular structure. Compounds 3 and 6 are based on a
fairly rigid 1,4 glycosydic linkage (secondary alcohol) and there-
fore can adopt a limited number of conformations in solution. The
flexibility of the 1,6 linkage allows for higher conformational
diversity, permitting the formation of fundamentally different
nanostructures.
detail using dimer 2 that forms well-defined, disperse, and stable
needle-like structures (Figure 2B). 2-S-HFIP presents an ordered
morphology as it showed intense birefringence under polarized
light, typical of anisotropic materials (Figure S7). Moreover,
staining with Congo red,18 a commonly-used dye to detect highly-
ordered amyloid fibrils, gave intense gold-green birefringence
(Figure S8). Dialysis using a higher concentration of 2 (2 mg
mL−1) led to the formation of nanofibers (Figure 2B-a), likely due
to the further association of the spherical particles existing in the
diluted solution. The solvent exchange method generated longer
needles when a lower concentration of compound 2 was employed
(0.1 mg mL−1) (Figure 2B-b). A higher HFIP content (20%) did
not change the shape or length of the supramolecular structures
(Figure 2B-c). In this case, the selective solvation properties of
HFIP, in a HFIP–H2O system,19 result in a similar local HFIP
concentration, limiting aggregation diversity. A similar elongated
morphology was obtained when isopropyl alcohol was used in-
stead of HFIP (Figure 2B-d) and a gel-like microwire material
was obtained in acetone (Figure 2B-f). The diversity observed is
ascribed to the different conformations adopted by compound 2,
when solvated by different solvents. In particular, the well-known
ability of HFIP to cluster the hydrophobic regions of peptides and
affect their folding (HFIP-induced enhancement of the hydropho-
bic effect)19-20 is responsible for the dramatic differences of the
generated nanostructures.
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Figure 1. Chemical structure of well-defined oligosaccharides (A) and illustration of sample preparation methods (B). The sample names
indicate the sugar oligomer (e.g. 2), the assembly method (D, S, or F), and the solvent used (e.g. HFIP). For example, 2-S-HFIP means
compound 2 prepared by solvent switch method with HFIP as good solvent.
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Figure 2. (A) Supramolecular structure formation with two different methods. (a-f) TEM images (scale bars: 100 nm) of samples prepared
by dialysis method (0.1 mg mL−1) for (a) 1-D, (b) 2-D, (c) 3-D, (d) 4-D*, (e) 5-D, and (f) 6-D*. *0.01 mg mL−1 due to poor solubility of
the starting material. (g-l) SEM images (scale bars: 2 µm) of samples prepared by solvent-switch method for (g) 1-S-HFIP-low (0.1 mg
mL−1), (h) 2-S-HFIP, (i) 3-S-HFIP, (j) 4-S-DMAc, (k) 5-S-HFIP, and (l) 6-S-DMAc. (B) Screening of assembly conditions for com-
pound 2. (a) TEM image (scale bar: 500 nm) for 2-D-high (2 mg mL−1). (b-f) SEM images (scale bars: 2 µm) for (b) 2-S-HFIP-low (0.1
mg mL−1), (c) 2-S-HFIP-20%, (d) 2-S-iPrOH-20%, (e) 2-S-DMAc, and (f) 2-S-Ace-20%. If not mentioned, the standard concentration
for the solvent switch method (S) is 2 mg mL−1 and the content of organic solvent is 2%.
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Real-time measurement. The self-assembly of 2-S-HFIP was
captured in real-time using bright-field microscopy (Figure 3,
Movie S1) by injecting a freshly-prepared solution into a cell
counting slide. Needle-like structures diffuse from the HFIP
droplets containing the oligosaccharide into the surrounding
water. The contact between the needles and a second HFIP droplet
(Figure 3, time 06:52) disrupt the droplet to release the oligosac-
charide and results in further needle growth. Surprisingly, glycan-
containing HFIP droplets are intensely fluorescent. We believe
that this phenomenon is the result of the formation of supramo-
lecular chromophores within the material, as previously observed
for self-assembled peptides, nucleic acids, and amino acids.17, 21
An extended π-conjugation system and/or charge delocalization
through a dense hydrogen-bonding network are generally respon-
sible for this behavior.21b
Photophysical characterization. Confocal microscopy anal-
ysis of different morphologies revealed that thin films prepared by
direct evaporation of a glycan solution in HFIP on a slide glass (2-
F-HFIP) emit strongly in four different channels (Figure 4A)
upon visible light irradiation. Films prepared in other organic
solvents showed a similar fluorescence behavior (Figure S10).
Aggregates obtained via the solvent switch method are only week-
ly emissive (Figure 4A). This observation agrees with the supra-
molecular chromophore hypothesis, since emission intensity is
strong in organic solvents, where a dense H-bonding network is
favored and quenching occurs when the H-bonding pattern is
disrupted by water. The morphology of these materials was fur-
ther probed with X-ray powder diffraction (XRD) (Figure. 4B). 2-
S-HFIP exhibited sharp peaks, as typical for crystalline struc-
tures; in contrast, 2-F-HFIP shows broad peaks. This confirms
the drastic change in morphology upon interaction with water (2-
S-HFIP). To better evaluate the causes of this phenomenon,
compounds (7-11) were prepared. To probe the importance of
aromatic groups for the emissive behavior, compound 7 was
synthesized. This amphiphilic, partially methylated analogue
allows for the formation of a dense hydrogen bonding network, in
the absence of aromatic groups. Upon film formation (7-F-HFIP),
compound 7 showed a similar optical behavior, confirming that
the optical properties are not merely a result of π-π stacking.
Figure 3. Real-time merged bright-field (scale of gray) and fluo-
rescence (magenta) images illustrate the self-assembly process for
2-S-HFIP. Excitation wavelength at 405 nm and detection range
410-676 nm (scale bar: 20 µm).
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Figure 4. (A) Confocal microscopy images of 2 prepared by HFIP film-forming F (scale bars: 100 µm), solvent-switch S (scale bars: 10
µm), and compounds 7-11 prepared by film-forming method (scale bars: 100 µm) in four different channels (blue(ex/em): 405/451 nm,
green: 488/529 nm, yellow: 561/597 nm, and red: 633/709 nm). (B) XRD profiles of 2-F-HFIP (red) and 2-S-HFIP (black) and com-
pounds 7-11.
Compounds 8-10 are fully functionalized, blocking the formation
of a dense hydrogen bonding network within the material. Differ-
ent substituents (Bn vs Me vs Ac) were tested. Surprisingly, con-
focal microscopy analysis showed emissive behavior for com-
pound 8-F-HFIP and 9-F-HFIP. We suspect that such com-
pounds, even in the absence of a strong hydrogen bonding net-
work, maintain a self-organization tendency. On the other hand,
the per-acetylated analogue 10, as well as the fully deprotected
compound 11, showed no emission. XRD analysis of all the mate-
rials suggested a correlation between the broad XRD profile and
the emissive behavior. Similarly, the appearance of sharp peaks in
the XRD profiles, indicating high crystallinity, is associated with
emission quenching.
of the absorption spectrum is not observed for compound 2 in
solution, nor for the low emissive, crystalline sample 2-S-HFIP
(Figure 5A). Excitation spectra (Figures S13 and S14) confirmed
that the emissive species are linked to this spectral region (350 –
500 nm). Emission quantum yield was calculated for 2-F-HFIP
(Ф(λex = 360 nm) = 0.85 ± 0.01 %). Moreover, unlike commonly-used
dyes, where the emission peak position is independent of the
excitation wavelength, the emission spectrum of 2-F-HFIP is
drastically affected by the excitation wavelength (Figure 5B). A
broad fluorescence emission profile was observed with maxima
shifting from 410 to 490 nm as the excitation is changed from 340
to 410 nm. This red edge excitation shift (REES) is a common
phenomenon observed in graphene oxide,21c ionic liquids,21d and
highly ordered assemblies,17 suggesting potential applications of
self-assembling oligosaccharides for optical devices, semiconduc-
tors, and nanotechnology.1d, 17, 21a, 21b
Further photophysical characterization showed a broad absorption
band for compound 2-F-HFIP, associated with the formation of
new self-assembled entities upon film formation. The broadening
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Figure 5. (A) Absorption spectra of 2-F-HFIP, 2-S-HFIP (recorded for the solid samples), and compound 2 in HFIP solution. (B) Nor-
malized emission spectra of 2-F-HFIP at excitation wavelengths of 340, 350, 360, 370, 380, 390, 400, 410, 420, and 430 nm, showing the
red shifting of the emission maxima. Spectra acquired at RT.
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The authors declare no competing financial interests.
In conclusion, we successfully generated supramolecular struc-
tures from fully synthetic well-defined oligosaccharides, and
demonstrated that the fine-tuning of the oligosaccharide structure
has a tremendous effect on the material morphology. The three
We thank the Max-Planck Society and the Clore Scholarship
dimer and hexamer analogues with different glycosidic linkages
program for generous financial support. We thank Heike Runge,
and protective group patterns form similar nanospheres when
Dr. Oleksandr Savatieiev, Maria Hagen, Michaela Eder, Felix
generated by the slow dialysis method, whereas distinctive micro-
Fuchsberger, Eva Settels, Felix Hentschel, Olaf Niemeyer, Ingrid
structures are obtained with the fast solvent switch method. These
Zenke, Daniel Werner, Dr. Richard J. Fair, Alonso Pardo-Vargas,
compounds show unique optical properties such as broad emis-
and Reinhild Dünnebacke for technical support.
sion profiles and red edge excitation shift. Further studies to
modulate the fluorescent properties of such materials are currently
underway, with potential applications for optical devices and
nanotechnology. These findings suggest that synthetic oligosac-
charides are viable substrates for the fundamental study of the
forces that guide the polysaccharide aggregation in nature. For
example, tuning glycomaterial properties through the synthesis of
well-defined structures will be relevant for drug delivery systems,
where carbohydrate-carbohydrate interactions play a significant
role in cellular uptake.
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*martina.delbianco@mpikg.mpg.de and
peter.seeberger@mpikg.mpg.de
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‡These authors contributed equally.
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