A challenging target in the noncovalent synthesis of nanostructured functional materials is the formation of uniform features that exhibit well-defined properties, e.g., precise control over the aggregate shape, size, and stability. In particular, for aqueous-based one-dimensional supramolecular polymers, this is a daunting task. Here we disclose a strategy based on self-assembling discotic amphiphiles that leads to the control over stack length and shape of ordered, chiral columnar aggregates. By balancing out attractive noncovalent forces within the hydrophobic core of the polymerizing building blocks with electrostatic repulsive interactions on the hydrophilic rim we managed to switch from elongated, rod-like assemblies to small and discrete objects. Intriguingly this rod-to-sphere transition is expressed in a loss of cooperativity in the temperature-dependent self-assembly mechanism. The aggregates were characterized using circular dichroism, UV and 1H-NMR spectroscopy, small angle X-ray scattering, and cryotransmission electron microscopy. In analogy to many systems found in biology, mechanistic details of the self-assembly pathways emphasize the importance of cooperativity as a key feature that dictates the physical properties of the produced supramolecular polymers.
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Molecular self-assembly has emerged as a fascinating area in its own right (1, 2). A toolbox initially developed by supramolecular chemists quickly expanded into an interdisciplinary field aiming at the manipulation of matter at the molecular scale (3, 4). Up until recently self-assembly in dilute aqueous environments has predominantly dealt with linear amphiphiles that form closed structures (5–9), such as spherical micelles, cylindrical or rod-like micelles, and vesicles using, for example, phospholipids (10, 11), synthetic block copolymers (12, 13), or dendrimers (14). Morphological control in objects of defined size or shape, and transitions between different morphologies are increasingly well understood (15–18). Surprisingly, however, the generality of these concepts has not been translocated into another area of increasing interest, namely, the self-assembly of one-dimensional arrays. In that context the development of discotic monomers has proven to be a valuable route to allow for the synthesis of rod-like supramolecular polymers (19), whose potential applications in functional soft matter include electronics, biomedical engineering, and sensors (20–26). Considering the enormous interest in such systems, it is surprising that efforts to control the size and shape of nano- and micrometer size one-dimensional objects are rare (27–29); successful strategies rely on the use of templates (30, 31), end cappers (32), or selective solvent techniques (33).
In order to control the growth of aqueous one-dimensional supramolecular polymers, we propose to utilize electrostatic repulsive contributions in analogy to surfactant type self-assembly. However, rather than simply relying on solvophobic effects based on the lipophilic segments of the amphiphile, we use noncovalent polymerizable moieties to craft building blocks that are designed to code for “infinitely” long, chiral supramolecular architectures. Along with others (22, 28, 29, 34, 35), we are convinced that exploring the balance between attractive forces (dipole interactions, π-π stacking, and solvophobic effects) and repulsive interactions allows us to produce supramolecular materials with well-defined architectures and order parameters over several length scales. On the basis of that hypothesis, we hereby report a strategy to rationally control the shape, size, and stability of columnar assemblies in aqueous environments using subtle differences in the ionic character of C3-symmetrical discotic amphiphiles. This is a unique example for directional self-assembly in water whereby the supramolecular polymer shape and size can be dictated by Coulombic interactions. In line with our continuous efforts in elucidating the mechanisms of supramolecular polymerizations (36, 37), we have focused on correlating the morphological properties of the produced materials with the appropriate mechanistic details of the self-assembly pathways.
Results and Discussion
Design Concept and Synthesis.
The hydrophobic effect between insoluble apolar moieties and the steric and/or electrostatic repulsion in the polar head group are generally the major governing forces in the aqueous self-assembly of linear amphiphiles. The competition between those opposing forces, which itself is depending on the relative geometry of both moieties—the surfactant packing parameter—dictates the resultant morphology of the structures (10, 11). Mukerjee et al. (38) and Tanford (39) pioneered the idea of repulsive interactions between polar surfactant head groups being the dominant forces that constrain micelles to finite sizes. In analogy we propose the use of repulsive Coulombic forces in order to control the aqueous supramolecular polymerization of discotic amphiphiles into columnar assemblies of defined length.
The molecular design of our self-assembling unit is based on the well-studied C3-symmetrical benzene-1,3,5-tricarboxamide (BTA) core that directs the self-assembly into triple hydrogen-bonded helices (40–42). This moiety was extended with a fluorinated L phenylalanine and an aminobenzoate spacer, thereby significantly increasing the stability of the assemblies via additional hydrogen bonding, π-π interactions, and solvophobic effects (Fig. 1), while at the same time creating a hydrophobic pocket in the core of the discotic to shield the triple hydrogen-bonding motif. Our reason for introducing peripheral hydrophilic metal chelates complexes was twofold: A divergent synthetic approach for the C3-symmetrical discotics allowed the synthesis of three amphiphiles with increasing ionic character from a common intermediate (SI Appendix). At the same time complexation of a paramagnetic lanthanide, e.g. Gd(III), would open the route for the preparation of a unique class of supramolecular contrast agents for magnetic resonance imaging (Fig. 2).
Fig. 1.
Schematic representation of the self-assembly of discotic amphiphiles: The hydrophobic BTA core (solid circle) directs the self-assembly into a helical architecture; the hydrophobic, chiral amino acid substituents (dashed line) in the second layer determine the handedness and stability of the helix; the peripheral hydrophilic groups introduce an amphiphilic character to the design.
Fig. 2.
Schematic representations of the fluorinated discotic amphiphiles: the BTA core, chiral amino acid (L pentafluorophenylalanine), and aminobenzoate spacer are schematically depicted in green; the peripheral hydrophilic M(III) complexes (depicted in blue) introduce an increasingly pronounced “ionic character” (depicted in red) to the molecular building blocks: overall neutral M(III)-DOTA 1, singly charged M(III)-DTPA-N-MA 2, and doubly charged M(III)-DTPA 3 [for paramagnetic discotics 1a, 2, and 3a M(III) = Gd(III); for diamagnetic discotic 1b and 3b M(III) = Y(III)].
A common synthetic intermediate for all three discotic amphiphiles 1–3 was synthesized in four high yielding steps via standard amide coupling reactions using orthogonal protecting groups (SI Appendix). Thereafter two to three synthetic steps were necessary to couple the appropriate ligands onto the common intermediate, followed by complexation with the trivalent metal to yield the final discotic amphiphiles (SI Appendix). Compound 1 (Fig. 2) is based on the M(III)-DOTA (1,4,7,10-tetraazacyclododecane-N,N′,N′′,N′′′-tetraacetic acid) monoamide chelate, an overall charge-neutral complex. By switching to a DTPA (diethylenetriaminepentaacetic acid) derivative linked via one of the carboxylic acids, we introduce one remaining negative charge per chelated metal or three per discotic (2, Fig. 2). If the linker is attached to the ethylene bridge of the DTPA chelater, the complexation of a trivalent metal at close to neutral pH leads to two overall remaining charges per complex and the necessity for two counter cations (3, Fig. 2).
By increasing the ionic character of the peripheral M(III) complexes, we are aiming to introduce frustration in the one-dimensional growth of the stacks, an intriguing concept for discotic monomers whose core is designed to code for elongated rod-like aggregates. The motivation of the present work is to control the length and aspect ratio of the helical columnar self-assemblies, and we therefore focus the first part of our investigations on morphological characterization of the one-dimensional supramolecular polymers in aqueous solution.
Shape and Size of the Supramolecular Aggregates.
A powerful technique to determine the shape and size of colloidal dilute particulate systems is small angle scattering (43–47). The presence of peripheral metal complexes strongly increased the scattering power of the aggregates and enabled the investigation of dilute solutions by means of synchrotron small angle X-Ray scattering (SAXS).
Fig. 3 reports the SAXS profiles for the discotic amphiphiles 1a and 3a in citrate buffer solutions at different concentrations.* The shape of the aggregates can be directly derived from the slope of the SAXS profiles in the region 0.01 < q < 0.06 Å-1. Discotic 1a-based aggregates clearly show a q-1 slope (Fig. 3A), characteristic of rod-like objects. The aggregates can be described as noninteracting cylinders, and the profiles were fitted assuming a homogenous monodisperse cylindrical form factor (SI Appendix). The calculated rod radii of 3.1 nm are independent of the concentration and in agreement with extended chain structures of the flattened monomeric building blocks (R ∼ 2.9 nm). The lengths or the rods are 25 nm at lower concentrations and larger than 75 nm at 1 mM.
Fig. 3.
SAXS profiles for the fluorinated discotics 1a (A) and 3a (B) in citrate buffer (100 mM, pH 6).
In contrast, any characteristic slope indicating aggregate shape anisotropy is absent in the SAXS profiles from solutions of discotic 3a (Fig. 3B). The data measured at different concentrations could be fitted using a homogenous monodisperse spherical form factor (see SI Appendix), leading to calculated radii of 3.2 nm. Comparison with chain extended structures and a corresponding geometric radius of around 3.0 nm strongly suggests the presence of aggregates with an aspect ratio of close to 1.
By determining diffusion coefficients of the aggregated diamagnetic discotic amphiphile 3b in a deuterated succinate buffer (50 mM, “pH 6”), the Stoke–Einstein relation (48) allowed us to calculate hydrodynamic radii of the discrete objects of spherical size (Table 1). Their size is in agreement with values obtained from SAXS data for 3a. Assuming an interdisc distance of 3.5 Å (42), we were able to estimate the weight averaged degrees of polymerization (DPW) leading to molecular weights of about 50 kDa at a monomer concentration of 1 mM. On the other hand in the case of diamagnetic discotic 1b, very extensive line broadening in the 1H-NMR spectra and a complete loss of signals at room temperature resulted from the large degree of polymerization (> 200 according to SAXS) of the self-assembled rod-like aggregates.
Table 1.
1H-DOSY NMR data of stacks based on amphiphile 3b
3b [mM]
Dt (stacks) [10-10 m2 s-1]
RH (stacks) [10-10 m]
DPW
1
0.69
29
17
2
0.38
52
30
Final and definite evidence for successful control over one-dimensional stack length was obtained from cryogenic transmission electron microscopy (cryo-TEM) micrographs. The technique preserves the structural morphology of the self-assembled aggregates and avoids drying affects related to conventional TEM sample preparation. Rod-like morphologies are visible for supramolecular polymers based on building block 1a (Fig. 4). The 5-nm width of the rods are in good agreement with the SAXS data. In contrast, Fig. 5 shows that discotic 3a did produce the expected spherical objects with dimensions close to 5 nm at a 1-mM building block concentration (Fig. 6), which confirms the results from SAXS and diffusion ordered spectroscopy (DOSY) measurements. According to these findings, we have been able to obtain self-assembled discrete objects that can be considered the supramolecular equivalent of dendritic macromolecules (49, 50).
Fig. 4.
Cryo-TEM micrographs for self-assembled discotic amphiphile 1a (0.66 mM) vitrified at 288 K in citrate buffer (100 mM, pH 6); scale bar represents 50 nm.†
Fig. 5.
Cryo-TEM micrographs for discotic amphiphile 3a (1 mM) vitrified at 288 K in citrate buffer (100 mM, pH 6); scale bar represents 50 nm.
Fig. 6.
Schematic 3D representation of a stack of 11 monomers of 3a. (Left) Side view of the stack; (Right) top view.
Similarly to the self-assembly of linear amphiphiles we have used Coulombic interactions to introduce repulsive forces and restrict one-dimensional growth of supramolecular polymers. We are, however, not content with only determining the morphologies of the produced materials in solution. In order to fully investigate the governing forces in the aqueous self-assembly of discotic amphiphiles, we used spectroscopic data to elucidate the order in the columnar aggregates and study the mechanism by which the polymers grow via temperature-dependent measurements. In a recent review, we have emphasized the importance of differentiating self-assembly mechanisms for supramolecular polymers in analogy to the classification of traditional covalent polymers (36).
Self-Assembly Mechanism.
Optical spectroscopy has in the past proven to be a rich experimental source for elucidating the order in and structure of self-assembled systems (20, 41, 51–53). Circular dichroism (CD) spectroscopic data, in particular, show bisignate cotton effects for all three compounds in the same citrate buffer (100 mM, pH 6), which strongly suggest the presence of ordered aggregates (Fig. 7): We can therefore reliably postulate the formation of helical assemblies. Note that in order to make fair comparisons between the different compounds and at the same time relate the results of the optical measurements to the SAXS data, as well as the cryo-TEM micrographs, we used the same buffered conditions as described above (100 mM citrate buffer at pH 6).
Fig. 7.
Temperature-dependent CD spectra in a 100-mM citrate buffer at pH 6: (A) discotic 1a (5·10-6 M), (B) discotic 2a (2.5·10-6 M) and discotic 3a (20·10-6 M) and the resulting normalized and fitted CD cooling curves monitored at Dλ = 282 nm for discotic 1a, (E) λ = 283 nm for discotic 2a, (F) λ = 269 nm for discotic 3a. The lower three graphs show the normalized data as degree of aggregation Φn vs. temperature: 0 refers to the molecular dissolved state and 1 to a fully polymerized system; red lines represent the best fits (37, 54).
After heating the buffered solutions to a molecularly dissolved state, we recorded cooling curves and monitored the shape and intensity of the CD and UV/Vis spectra upon polymerization of the supramolecular aggregates (Fig. 7D–F). The extraordinarily high stability of the fluorinated discotic amphiphiles 1a–3a in aqueous buffered environments is indicated by the dilute conditions and very high temperatures required to fully depolymerize the aggregates. The importance of solvophobic effects and hydrophobic shielding become evident when comparing compounds 1a and 3a to their nonfluorinated equivalent. Aggregates based on the latter are about an order of magnitude less stable.
Striking is the difference in the cooling curves monitored at λmax of the individual compounds and performed at 1 K· min-1 in order to allow supramolecular polymerization to proceed under thermodynamic control (Fig. 7). The cooling curves for discotics 1a and 2 are clearly nonsigmoidal, which is indicative for a cooperative temperature dependent self-assembly, that can be described by a nucleation-elongation type mechanism (Fig. 7D and E). Two regimes can be distinguished: a thermodynamically less favored and nonordered nucleation regime at high temperatures, separated from the polymerization or growth regime by Te, the temperature below which elongation occurs. In strong contrast, compound 3a led to sigmoidal temperature-dependent profiles with a red-shifting negative CD band upon decreasing the temperature (Fig. 7F). There clearly is no positive cooperative mechanism operative, and at least on a macroscopic level—based on temperature-dependent CD profiles—we propose an isodesmic or equal K model to be dominating the self-assembly behavior.
These drastic changes in the supramolecular polymerization mechanisms were confirmed by UV/Vis spectroscopy (SI Appendix). The UV bands of the aromatic moities in the wedge of the discotics shift toward higher wavelengths, a strong indication for the formation of J aggregates or slipped arrangement of the peripheral chromophores. However, the red shifts that were observed upon aggregation are relatively small, and in these cases we prefer to rely on the more sensitive CD cooling curves for fitting procedures.
Various research groups, including ours, have reviewed models that allow the distinction between fundamentally different self-assembly mechanisms (36, 52, 54–56). Based on the van der Schoot model (54), reliable fitting procedures (37) can provide us with the thermodynamic parameters describing the processes involved. For the cooperative self-assembly of compounds 1a and 2, above Te the nucleation regime is characterized by a dimensionless activation constant Ka of 10-4 for 1a and 10-3 for 2. Below Te the growth regime can be described by the enthalpy change upon elongation (ΔHe), which is 40 kJ mol-1 for both building blocks 1a and 2. Another typical characteristic of these enthalpy-driven supramolecular polymerization mechanisms becomes evident when performing concentration-dependent experiments: The Te values shift to lower temperatures when decreasing the concentration of the monomer (SI Appendix).
Assuming an isodesmic mechanism (37, 54) in the self-assembly of compound 3a, the apparent association constant at 298 K is on the order of 5·105 M-1 in a concentration regime of 8 μM to 20 μM. Only a slight decrease to 3·105 M-1 is observed when switching to a 10-mM PBS buffer at pH 7.4 or a 50-mM succinate buffer at pH 6 (SI Appendix). The latter became relevant for 1H NMR spectroscopic measurements as its deuterated equivalent is commercially available. Similarly to supramolecular polymers based on 1a and 2, melting curves for stacks of 3a shift to lower temperatures upon dilution (SI Appendix).
Optical measurements strongly suggest that the increased ionic character of discotic amphiphile 3a compared to compounds 1a and 2 has led to the intended changes in the self-assembly behavior. Furthermore, we were able to correlate cooperative self-assembly processes to the formation of high molecular weight supramolecular polymers, producing high aspect ratio rod-like aggregates. In contrast, the absence of a cooperative mechanism led to a huge decrease in the degree of polymerization, yielding discrete objects with aspect ratios close to 1. This is in agreement with a theory that predicts a switch to anticooperativity with increased Coulombic repulsive interactions. This anticooperative mechanism is not distinguishable of an isodesmic process. The latter is a step-by-step reversible polycondensation—the equivalent in covalent polymer chemistry—which yields only moderate degrees of polymerization with large polydispersities, unless the binding affinity or conversion is extremely high. Hence, where 1a and 2 polymerize in a cooperative manner, yielding long elongated rods, the highly charged 3a polymerizes in an anticooperative manner yielding discrete objects.
This leaves us with finding further evidence for the assumption that solely Coulombic repulsive interactions are responsible for those drastic changes in the observed self-assembly mechanisms.
Frustrated Growth Induced by Coulombic Repulsive Forces.
At this stage we should point out that so far we have mainly worked in one specific buffer in order to make meaningful comparisons between various building blocks and characterization techniques. However, if electrostatic repulsive forces of the peripheral charged M(III)-DTPA complexes on discotic 3 are at the origin of the frustrated one-dimensional growth and possibly reduced order within the aggregates, we expected that increasing the ionic strength of the buffered environment, using an inert 1∶1 salt with highly hydrated counterions, should restore cooperative growth. In citrate buffered 0.2 M NaCl, the effect was not yet observed (SI Appendix). However, when we increased the salt concentration further to 0.5 M (Fig. 8), the CD spectrum and the shape of the cooling curve (Ka is 10-3 and ΔHe 35 kJ mol-1) were very reminiscent to the corresponding spectral data for the overall charge neutral, cooperatively assembling discotic 1a (Fig. 7A and D). Importantly, the restoration of cooperativity in the self-assembly of charged monomer 3a was also accompanied by the formation of high aspect ratio rod-like supramolecular polymers, clearly observed in cryo-TEM micrographs at high ionic strength (Fig. 9). Electrostatic screening is the most likely explanation for those findings and in line with the disruption of frustrated growth in Hartegrink’s multidomain peptide assemblies observed at a salt concentration of 1 M NaCl (28). In the field of linear-charged amphiphiles or ionic surfactant-like self-assemblies, salt-induced sharp sphere-to-rod micellar transitions were reported already about 20 years ago (57–59). By increasing the ionic strength of the aqueous environment, spherical charged micelles were able to grow into rod- or worm-like micelles at the same surfactant volume fraction. Similarly, polyelectrolytes—covalent macromolecules with charged ionizable groups—can behave like semiflexible polymers with ionic strength-dependent persistence length: Stiff cylinder-like conformations of a polyelectrolyte at low salt concentration can be collapsed into spherical globules or coils via electrostatic screening (60–65). More recently the importance of screening Coulomb interactions has also been reported for the self-assembly of virus capsids (66).
Fig. 8.
(A) Temperature-dependent CD spectra in a citrate buffer (100 mM, pH 6) and overall NaCl concentration of 0.5 M, of discotic 3a (7·10-6 M), and (B) the resulting normalized and fitted CD cooling curves monitored at λ = 276 nm.
Fig. 9.
Cryo-TEM micrographs for discotic amphiphile 3a (1 mM) vitrified at 288 K in citrate buffer (100 mM, pH 6) and overall NaCl concentration of 3 M (Left) and 5 M (Right); scale bar represents 50 nm.
Conclusions
By balancing out attractive forces based on dipole interactions, π-π stacking, solvophobic effects, with electrostatic repulsive interactions, we have managed the self-assembly of discotic amphiphiles into helical, columnar aggregates of controlled length. Whereas the hydrophobic core of the discotic building block determines the high stability of the aggregates, it is the peripheral ionic character of the hydrophilic metal complexes that has a drastic impact on the self-assembly mechanism and the resulting aspect ratio of the nanoscale objects. Subtle changes in the ionic character resulted in the abrupt loss of cooperativity: Coulombic repulsions led to frustrated growth and hence to the formation of objects of discrete size, as opposed to elongated rod-like columnar assemblies. We demonstrated that charge-charge repulsive interactions are the primary forces involved in the case of restricted growth by fully restoring cooperative growth via electrostatic screening.
In summary, the combination of positive molecular interactions on one hand and the use of Coulombic repulsive interactions on the other hand are both an extremely powerful tool in order to gain control over the targeted architectures. This approach paves the way for what we believe to be one of the grand challenges in supramolecular chemistry: controlling the shape and size of functional noncovalent polymers.
In more general terms, cooperativity is an increasingly intriguing concept for chemists (67), and it has become clear that its presence or absence in the self-assembly mechanism is a key feature in manipulating the physical properties of synthetic supramolecular polymers (36). This is in analogy to the central role of cooperativity in many biological systems, such as amyloid fibril proliferation (68, 69), itself linked to clinical disorders ranging from Alzheimer’s disease to type II diabetes (70).
Materials and Methods
Unless stated otherwise, all reagents and chemicals were obtained from commercial sources at the highest purity available and used without further purification. Water was demineralized prior to use. Reactions were conducted under an argon atmosphere using standard Schlenk line techniques unless otherwise specified. Flash chromatography was performed on a Biotage flash chromatography system. 1H-NMR, 13C, and 19F-NMR spectra were recorded on Varian Mercury 400 and 200 spectrometers at 298 K. The 1H-DOSY NMR experiments were recorded on a Varian Unity Inova 500 spectrometer equipped with a 5-mm indirect-detection pulsed field gradient (ID-PFG) probe from Varian. Matrix-assisted laser desorption/ionization mass spectra were obtained on a PerSeptive Biosystems Voyager DE-PRO spectrometer. Liquid chromatography-mass spectrometry (LC-MS) analyses were performed using a Shimadzu SCL-10 AD VP series HPLC coupled to a diode array detector (Finnigan Surveyor PDA Plus detector, Thermo Electron Corporation) and an Ion-Trap (LCQ Fleet, Thermo Scientific). GdIII and YIII contents were determined by means of inductively coupled plasma atomic emission spectrometry (ICP-AES) conducted by the MiPlaza Materials Analysis laboratories (Philips Research Europe) in Eindhoven, The Netherlands. Cryogenic transmission microscopy measurements were performed on the cryoTitan TEM (FEI), equipped with a field emission gun (FEG) operating at 300 kV. Images were recorded using a 2k × 2k Gatan CCD camera equipped with a post column Gatan energy filter (GIF). CD and UV/Vis measurements were performed on a Jasco J-815 spectropolarimeter where the sensitivity, time constant, and scan rate were chosen appropriately. Corresponding temperature-dependent measurements were performed with a Jasco PTC-348WI Peltier-type temperature controller, with a temperature range of 263–383 K and adjustable temperature slope. The SAXS measurements were performed at the Dutch-Belgian BM26B beamline at the European Synchrotron Radiation Facility in Grenoble, France. A sample-to-detector distance of 6.23 m was used together with an X-ray photon wavelength of 1.24 Å. The observed q range was 7 × 10-3Å-1 ≤ q ≤ 0.12 Å-1, where q is the magnitude of the scattering vector q = (4π/λ) sin θ, and where λ is the X-ray wavelength and θ is half of the scattering angle. SI Appendix provides all the reaction schemes, detailed experimental procedures and characterization, additional CD and UV/Vis data, as well as 1H-DOSY NMR and SAXS procedures.
Acknowledgments.
The authors thank Prof. Paul van der Schoot, Dr. Maarten Smulders, and Dr. Tom de Greef for discussions, Dr. Thomas Hermans for help with the DOSY measurements, Tristan Mes, Dr. Michel van Houtem, and Wilco Appel for assisting with the SAXS measurements in Grenoble, Dr. Henk Keizer for providing DOTA-NHS, Bas de Waal, Dr. Kelly van den Hout, and Dr. Cameron Lee for helpful suggestions during the synthesis, Dr. Koen Pieterse for the 3D modeling, and Dr. Martijn Veld for the artwork. We also thank Dr. Sander Langereis and Jeanette Smulders (MiPlaza Materials Analysis laboratories, Philips Research Europe) for carrying out ICP-AES measurements. The authors thank IBOS (Integration of Biosynthesis and Organic Synthesis, Project 053.63.310) and Marie Curie Actions FP7 (SahnMat, PIEF-GA-2009-235914) (to P.B.) for funding, and the ESRF and The Netherlands Organisation for Scientific Research for providing the beam time.
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The authors thank Prof. Paul van der Schoot, Dr. Maarten Smulders, and Dr. Tom de Greef for discussions, Dr. Thomas Hermans for help with the DOSY measurements, Tristan Mes, Dr. Michel van Houtem, and Wilco Appel for assisting with the SAXS measurements in Grenoble, Dr. Henk Keizer for providing DOTA-NHS, Bas de Waal, Dr. Kelly van den Hout, and Dr. Cameron Lee for helpful suggestions during the synthesis, Dr. Koen Pieterse for the 3D modeling, and Dr. Martijn Veld for the artwork. We also thank Dr. Sander Langereis and Jeanette Smulders (MiPlaza Materials Analysis laboratories, Philips Research Europe) for carrying out ICP-AES measurements. The authors thank IBOS (Integration of Biosynthesis and Organic Synthesis, Project 053.63.310) and Marie Curie Actions FP7 (SahnMat, PIEF-GA-2009-235914) (to P.B.) for funding, and the ESRF and The Netherlands Organisation for Scientific Research for providing the beam time.
Notes
This article is a PNAS Direct Submission.
*Compound 2 was not soluble enough to enable morphological characterization at high concentrations.
†
The dark, ill-defined and larger spots are contamination in the specimen from ice crystal formation.
Authors
Affiliations
PolBesenius
Institute of Complex Molecular Systems and Laboratory of Macromolecular and Organic Chemistry, Eindhoven University of Technology, P.O. Box 513, 5600 MB Eindhoven, The Netherlands;
Laboratory of Materials and Interface Chemistry and Soft Matter CryoTEM Research Unit, Department of Chemical Engineering and Chemistry, Eindhoven University of Technology, P.O. Box 513, 5600 MB Eindhoven, The Netherlands; and
Institute of Complex Molecular Systems and Laboratory of Macromolecular and Organic Chemistry, Eindhoven University of Technology, P.O. Box 513, 5600 MB Eindhoven, The Netherlands;
Institute of Complex Molecular Systems and Laboratory of Macromolecular and Organic Chemistry, Eindhoven University of Technology, P.O. Box 513, 5600 MB Eindhoven, The Netherlands;
To whom correspondence should be addressed. E-mail: [email protected].
Author contributions: P.B., H.M.J., A.R.A.P., and E.W.M. designed research; P.B. performed research; G.P., P.H.H.B., and H.M.J. contributed new reagents/analytic tools; P.B. and G.P. analyzed data; and P.B. wrote the paper.
Competing Interests
The authors declare no conflict of interest.
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P. Besenius,
G. Portale,
P.H.H. Bomans,
H.M. Janssen,
A.R.A. Palmans,
& E.W. Meijer,
Controlling the growth and shape of chiral supramolecular polymers in water, Proc. Natl. Acad. Sci. U.S.A.107 (42) 17888-17893,https://doi.org/10.1073/pnas.1009592107(2010).
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In sophisticated auditory–motor learning such as musical instrument learning, little
is understood about how brain plasticity develops over time and how the related individual
variability is reflected in the neural architecture. In a ...The auditory and motor neural systems are closely intertwined, enabling people to
carry out tasks such as playing a musical instrument whose mapping between action
and sound is extremely sophisticated. While the dorsal auditory stream has been shown
to ...
Age-related cognitive decline is associated with metabolic, vascular, and inflammatory
changes, making it challenging to distinguish primary causes from secondary (downstream)
effects. This study demonstrates that brain aging follows a ...Understanding the key drivers of brain aging is essential for effective prevention
and treatment of neurodegenerative diseases. Here, we integrate human brain and physiological
data to investigate underlying mechanisms. Functional MRI analyses across four ...
