Article pubs.acs.org/Langmuir
Tunable Self-Assembled Peptide Amphiphile Nanostructures Qingbin Meng,† Yingying Kou,† Xin Ma,‡ Yuanjun Liang,† Lei Guo,† Caihua Ni,‡ and Keliang Liu*,† †
Beijing Institute of Pharmacology and Toxicology, 100850, Beijing, P. R. China School of Chemical and Material Engineering, Southern Yangtze University, 214122, Wuxi, P. R. China
‡
ABSTRACT: Peptide amphiphiles are capable of self-assembly into a diverse array of nanostructures including ribbons, tubes, and vesicles. However, the ability to select the morphology of the resulting structure is not well developed. We examined the influence of systematic changes in the number and type of hydrophobic and hydrophilic amino acids on the self-assembly of amphiphilic peptides. Variations in the morphology of self-assembled peptides of the form X6Kn (X = alanine, valine, or leucine; K = lysine; n = 1−5) are investigated using a combination of transmission electron microscopy and dynamic light scattering measurements. The secondary structures of the peptides are determined using circular dichroism. Self-assembly is controlled through a combination of interactions between the hydrophobic segments of the peptide molecules and repulsive forces between the charged segments. Increasing the hydrophobicity of the peptide by changing X to a more lipophilic amino acid or decreasing the number of hydrophilic amino acids transforms the self-assembled nanostructures from vesicles to tubes and ribbons. Changes in the hydrophobicity of the peptides are reflected in changes in the critical micelle concentration observed using pyrene probe fluorescence analysis. Self-assembled materials formed from cationic peptide amphiphiles of this type display promise as carriers for insoluble molecules or negatively charged nucleic acids in drug or gene delivery applications.
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INTRODUCTION Molecular self-assembly is a widely used method for fabricating nanoscale materials. Natural molecular self-assembled systems are composed of lipids, peptides, and nucleic acids and are essential to cell and organism function. Materials self-assembled from peptides have drawn a great deal of research attention over the past few decades due to their biocompatibility and potential medical applications.1−5 These include tissue repair scaffolds, hydrogels, drug delivery vehicles, and structural templates for inorganic materials.6−14 Surfactant-like peptides with at least one charged amino acid at one end and a string of hydrophobic amino acids at the other represent a specific class of peptide building blocks. Under various conditions, surfactant-like peptides self-assemble into a wide range of nanostructures including tubes, fibers, and vesicles.6,15−19 Zhang’s group described the self-assembly behavior of a series of surfactant-like peptides containing the same six hydrophobic amino acids at the tail and one or two hydrophilic amino acids at the head. Quick-freeze/deep-etch transmission electron microscopy (TEM) was used to observe the morphology of the selfassembled peptides, and well-ordered nanostructures were obtained.6,7,15,16 The same group also modified the composition of the hydrophobic tail to design a cone-shaped peptide AcGAVILRR-NH2 that assembled into donut-shaped nanostructures.20 Lu et al. studied the influence of tail length on selfassembly behavior in AnK peptides and described an interesting structural transition from lamellar sheets to nanofibers when the tail length was increased.19 The interfacial self-assembly of several surfactant-like peptides has also been studied.21,22 © 2012 American Chemical Society
The self-assembly process is controlled by many factors including hydrophobic interactions, electrostatic interactions, inter- or intramolecular hydrogen bonds, and van der Waals forces. For surfactant-like peptides, hydrophobic and electrostatic interactions are typically dominant forces regulating the self-assembly process. Changing the length of the hydrophobic region or modifying the charge of the hydrophilic region both affect the morphology of peptide self-assembly.17,19,23 Selfassembly of nanostructures from surfactant-like peptides may be modulated through a synergistic combination of the two major driving forces. We followed up the self-assembly behavior of X6Kn series peptides by changing the identity of the hydrophobic amino acids X and the number of hydrophilic amino acids and systematically investigated the morphology of structures formed from the peptides. The cationic peptide surfactant X6Kn self-assembled to form ordered nanostructures with the hydrophilic residues K exposed to the surrounding aqueous environment and the hydrophobic residues packed inside the structure.6,15,16 We modified the character of the peptides from surfactant-like to “block” peptides by prolonging the hydrophilic amino acid chain length. The exterior amino acids were positively charged at neutral pH and able to combine with DNA, RNA, or other negatively charged molecules through electrostatic interactions. Therefore, the self-assembled materials might be useful as carriers in drug or gene delivery. Received: January 22, 2012 Revised: February 17, 2012 Published: February 21, 2012 5017
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Table 1. Peptide Sequences and ESI-MS Characterization Results theoretical mass
peptide sequence Ac-AAAAAAK-NH2 (A6K) Ac-AAAAAAKK-NH2 (A6K2)
614 742
Ac-AAAAAAKKK-NH2 (A6K3)
870
Ac-VVVVVVKK-NH2 (V6K2)
910
Ac-VVVVVVKKK-NH2 (V6K3)
1038
Ac-VVVVVVKKKK-NH2 (V6K4) Ac-LLLLLLKK-NH2 (L6K2)
1166 994
Ac-LLLLLLKKK-NH2 (L6K3) Ac-LLLLLLKKKK-NH2 (L6K4) Ac-LLLLLLKKKKK-NH2 (L6K5)
1123 1251 1379
observed mass (m/z) 614.5((M + H)+) 371.9((M + 2H+)/2), 742.9((M + H)+) 436.0((M + 2H+)/2) 870.9((M + H)+) 892.8((M + Na)+) 456.0((M + 2H+)/2) 910.7((M + H)+) 520.3((M + 2H+)/2) 1039.2((M + H)+) 584.2((M + 2H+)/2) 498.3((M + 2H+)/2) 995.2((M + H)+) 562.3((M + 2H+)/2) 626.5((M + 2H+)/2) 690.6((M + 2H+)/2)
purity (%) 98.5 98.2 98.8
99.6 99.0 97.3 99.2 97.2 98.9 97.1
Figure 1. Molecular structures of individual amphiphilic peptides. Color code: carbon, blue; hydrogen, gray; oxygen, red; nitrogen, yellow. Lengths of the peptides in their extended conformations are 2.7 (A6K), 3.2 (A6K2, V6K2, L6K2), 3.6 (A6K3, V6K3, L6K3), 3.9 (V6K4, L6K4), and 4.3 nm (L6K5).
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EXPERIMENTAL SECTION
Materials. Protected amino acids (Fmoc-Ala-OH, Fmoc-Val-OH, Fmoc-Leu-OH, and Fmoc-Lys(Boc)-OH), O-(1H-benzotriazole-1-yl)N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU), and anhydrous N-hydroxybenzotriazole (HOBt) were purchased from GL Biochem (Shanghai) Ltd. and used as received. Rink amide resin (from Tianjing Nankai Hecheng Sci. & Tech. Co. Ltd.) and N,N′diisopropyl ethylamine (DIEA, Acros) were used as received. Pyrene was obtained from Alfa Aesar and recrystallized twice. Other reagents were analytical grade or better and used without further purification. Water was obtained from a Millipore water purification system and had a minimum resistivity of 18.2 MΩ cm. Synthesis of Amphiphilic Peptides. All peptides were synthesized following the general procedure for Fmoc chemistry of solid-phase peptide synthesis using natural L-amino acids on rink amide resin. The C termini of the peptides were amidated, and the N termini were acetylated, thus generating a net positive charge at neutral pH originating from the lysine residue side chains. Briefly, HOBt/HBTU and DIEA were used as coupling reagents. The coupling reaction was monitored using a ninhydrin assay. Deprotection was performed using 25% piperidine in DMF for 5 min and then for another 25 min at room temperature, respectively. The peptides were cleaved from the resin using trifluoroacetic acid/mcresol/H2O in a 95:2.5:2.5 volume ratio. The peptides were purified and analyzed using RP-HPLC (Shiseido C18 column, 150 × 4.6 mm, 5 μm), and the purities of all peptides were over 95%. The peptides were characterized using ESI-MS. CD Spectroscopy. Secondary structures were analyzed based on ellipticity spectra recorded between 190 and 270 nm using a CD spectrometer (MOS-450, BioLogic). Each peptide was dissolved in water at a concentration of 0.2 mM and pipetted into a cuvette with a 1 mm path length. A reference spectrum of water was subtracted from the raw data before performing molar ellipticity calculations using the formula [θ]λ = θobs × 1/(10Lcn) in which [θ]λ = molar ellipticity at λ in deg cm2 dmol−1, θobs = observed ellipticity at λ in mdeg, L = path
Figure 2. CD spectra of the peptides, revealing consistent random-coil structure. length in cm, c = concentration of peptide in M, and n = number of amino acids in the peptide.24 TEM. TEM observations were performed on a Hitachi H-7650 instrument at an acceleration voltage of 80 kV. To prepare the TEM samples, 20 μL of aqueous 1.0 mg mL−1 peptide solution was deposited onto a carbon-coated copper EM grid. After 30 s the excess fluid was removed and the grid was negatively stained with 2% (w/v) aqueous uranyl acetate for 5 min. The copper grid was air dried prior to insertion in the microscope. DLS. Size distributions of self-assembled nanostructures were determined using DLS on a ZS-90 instrument (Malvern, U.K.) at 25 °C. The samples consisted of 0.2 mL of 1.0 mg mL−1 peptide solution placed in a low volume cuvette and equilibrated for 2 min prior to measurement. Each sample was measured at least 3 times. Fluorescence Measurements. A series of peptide solutions in water were prepared with concentrations ranging from 1.0 μmol to 50 mmol. A 1 μL aliquot of 2 mM pyrene dissolved in ethanol was added to 1.0 mL of each peptide aqueous solution and shaken vigorously. Pyrene fluorescence measurements were obtained using an LS-55 spectrophotofluorimeter (Perkin-Elmer) at 25 °C. The excitation wavelength was 334 nm. The region from 360 to 440 nm 5018
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was examined at a scan speed of 300 nm min−1. A total of five characteristic peaks were observed for each sample. The cmc was determined from a plot of the intensity ratio of the peak near 373 nm (I1) and the peak near 383 nm (I3) as a function of concentration.
spectrometry (ESI-MS) and reverse-phase high-performance liquid chromatography (RP-HPLC) with the correct molecular weight and high purity (>97%). Peptide sequences and their theoretical and observed masses are listed in Table 1. The secondary structures of the peptides were investigated using circular dichroism (CD) (Figure 2). The CD spectra exhibited a negative peak between 196 and 201 nm and a wide shoulder near 222 nm, which is not characteristic of either αhelix or β-sheet structures. However, the shoulder at 222 nm indicated some α-helical conformation and was slightly more pronounced for L6Kx than V6Kx or A6Kx.25 On the basis of the CD spectra the secondary structure of the peptides was classified as irregular.26 All of the peptides possessed similar secondary structures but self-assembled into a variety of nanostructures at a concentration of 0.2 mM in water. Figure 3 is a collection of negative-stained TEM images of the self-assembled peptides. The peptide structures consisted of a hydrophobic segment containing 6 identical amino acids and a hydrophilic segment containing 1−5 lysine residues.
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RESULTS AND DISCUSSION We prepared a series of peptides denoted X6Kn in which X = alanine, valine, or leucine and n = 1−5. The peptides were synthesized using standard Fmoc chemistry solid-phase synthesis, and the series included A6K, A6K2, A6K3, V6K2, V6K3, V6K4, L6K2, L6K3, L6K4, and L6K5. The extended conformation peptide structures simulated by discovery studio 2.1 are illustrated in Figure 1. The C-terminus of each peptide was amidated, and the N-terminus was acetylated, leaving the ε-amino group of lysine as the only dissociable functional group present in the series and ensuring that the peptides were positively charged when dissolved in water. As shown in Table 1, all peptides were characterized by electrospray-ionization mass
Figure 3. (A) TEM images of self-assembled nanostructures formed by A6K, A6K2, A6K3, V6K2, V6K3, V6K4, L6K2, L6K3, L6K4, and L6K5 at a concentration of 1.0 mg mL−1 in water. (B) TEM images of self-assembled nanostructures formed by A6K3, V6K4, L6K5, V6K3, and L6K3 under different concentrations (0.1, 0.5, and 2.0 mg mL−1). Samples were negatively stained with uranyl acetate. Prior to TEM characterization, peptide solutions were stored at least for 24 h at 4 °C. 5019
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The 5 nm diameter nanotube structures formed by the peptides A6K, V6K2, and L6K3 are clearly visible in Figure 3A. The nanotube diameters were quite uniform, and the lengths ranged from hundreds of nanometers to micrometers. The selfassembly behavior of A6K and V6K2 was similar to that previously reported.16,19,25 Incorporation of an additional lysine in A6K2, V6K3, and L6K4 resulted in formation of nanovesicles of 30−40, 40−50, and 50−60 nm diameters. TEM images of peptides A6K3, V6K4, and L6K5 revealed irregular aggregates. As shown in Figure 3B, the ordered self-assembly cannot be observed at various concentrations for A6K3, V6K4, and L6K5. Yet, V6K3 and L6K3 can still form nanovesicles and nanotubes under these concentrations, respectively. The morphology of self-assembled peptides did not change under different concentration in the range of 0.1−2.0 mg mL−1 (Data of other peptides were not shown). When the peptides were dissolved in water, the hydrophobic regions spontaneously aggregated through hydrophobic interactions. The aggregates were further stabilized by hydrogen bonding between the backbones and side groups. The positively charged hydrophilic regions were exposed to the surrounding water and experienced repulsion due to electrostatic forces. Furthermore, the packing hindrance originated from the hydrophilic regions could not be neglected when the size of hydrophilic group was relatively big, which also resulted in the repulsion effect. Combination of the hydrophobic and electrostatic interactions and the hindrance effect determined the morphology of the nanostructures. The most hydrophobic sequence was L6Kx, followed by V6Kx and A6Kx. This coincides with the order of lipophilicity parameters (log P) reported by Wu.27 When x was 1, A6K was soluble and self-assembled into nanotubes while V6K and L6K were both insoluble. When x was 2, the peptides were all soluble. L6K2 formed ribbons with a length of several micrometers, while V6K2 formed nanotubes, and A6K2 formed vesicles. The nanostructures were clearly related to the composition of the peptides, suggesting this is an effective method for tuning peptide self-assembly. In the peptides A6K2, V6K2, and L6K2 the hydrophilic region was equivalent and the organization of the self-assembled nanostructures was solely dependent on the identity of the amino acid comprising the hydrophobic region. The most hydrophobic residue (L) formed a tightly aggregated ribbon structure, while the less hydrophobic residues formed tubes or vesicles. The number of hydrophilic K residues determined both the solubility and the occurrence of self-assembly. If the hydrophilic contribution was insufficient the peptide would not form self-assembled structures due to low solubility. However, the well self-assembly behavior also was not detected through TEM with highly soluble peptides such as A6K3, V6K4, and L6K5. Dynamic light scattering (DLS) was used to measure the size distribution of the nanostructures and confirm their presence in solution. Figure 4A is a plot of the size distributions observed for several of the peptide solutions. A6K solutions contained 40−80 and 150−350 nm particles, while V6K2 and L6K3 solutions contained particles with sizes ranging from 40 to 3000 nm. The ribbons formed by L6K2 were 300−700 nm in size. The size distributions of the vesicles formed by some of the peptides are depicted in Figure 4B. A6K2, V6K3, and L6K4 all exhibited single narrow distributions between 20 and 70, 70 and 110 nm, and 250 and 500 nm, respectively. The nanostructures observed in the TEM images appeared smaller since they were in a dry state. The vesicles were more uniform in size than the nanotubes because the variety of tube lengths
Figure 4. (A) Size distribution of self-assembled ribbons and nanotubes formed by A6K, V6K2, L6K3, and L6K2. (B) Size distribution of self-assembled vesicles formed by A6K2, V6K3, and L6K4.
resulted in a relatively broad distribution. DLS did not provide an accurate size determination for nanostructures such as nanotubes, ribbons, and vesicles but could be used to demonstrate their existence in solution. We were interested in whether the morphology of the nanostructures formed by relatively low molecular weight peptides could be controlled by the composition of the hydrophilic and hydrophobic segments in the same way that composition and solvent properties are used to tune the morphology of nanostructures formed during self-assembly of block copolymer materials.28,29Self-assembly should occur when the concentration of the solution is above the critical micelle concentration (cmc), and the cmc is related to the hydrophobicity of the compound. Pyrene is a useful probe of the polarity of the microenvironment around nanostructures because the intensity ratio I1/I3 of two of its fluorescence peaks decreases drastically when the molecule is transferred from a hydrophilic to a hydrophobic environment.23,30,31 Except for the relatively hydrophilic A6K3 and L6K5, the fluorescence intensity ratio of pyrenecontaining peptide solutions decreased with increasing peptide concentration (Figure 5). At lower concentrations, I1/I3 5020
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concentrations, I1/I3 linearly decreased with increasing concentration, indicating formation of hydrophobic microenvironments around the pyrene. The cmc values were obtained from the intersection of the two regions (Table 2). For a given hydrophobic segment composition, the cmc value was highest for the irregular aggregates, followed by the vesicles and the nanotubes and ribbons. The schematic diagram in Figure 6 illustrates the proposed self-assembly mechanism. The ratio of hydrophilic to hydro-
Figure 6. Schematic illustration of peptide self-assembly. Increasing the hydrophilicity shifted the morphology of the structures from tight nanotubes to lose vesicles to irregular aggregates.
phobic segment size was the main factor influencing the morphology of the nanostructures, and the synergistic effect of hydrophobic and electrostatic interactions and the hindrance effect controlled the behavior of self-assembly.
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CONCLUSIONS The self-assembly of a series of amphiphilic peptides was systematically investigated. The morphologies of the nanostructures were related to the peptide sequence. The peptides A6K, V6K2, and L6K3 formed nanotubes in aqueous solution, A6K2, V6K3, and L6K4 formed vesicles, and A6K3, V6K4, and L6K5 formed irregular aggregates. Peptides with identical hydrophobic segments but a greater number of hydrophilic lysine residues had a higher cmc and tended to form vesicles rather than nanotubes. Those peptides with the highest cmc values or in which the cmc was not within the concentration range examined did not form regular self-assembled structures. The secondary structures of the peptides were all irregular. The self-assembly behavior was controlled by the combined effects of hydrophobic and electrostatic interactions and the hindrance effect established by the peptide sequence. By changing the peptide sequence, the morphology of the self-assembled peptides could be tuned, providing a useful means of designing new peptide nanomaterials.
Figure 5. Plots of pyrene I1/I3 ratio versus concentration for A6K, A6K2, and A6K3 (top), V6K2, V6K3, and V6K4 (middle), and L6K2, L6K3, and L6K4 (cottom). Dotted lines indicate cmc values.
Table 2. Morphology and Fluorescence-Determined cmc Values of Self-Assembled Structures peptide
morphology of self-assembly
cmc value (mM)
A6K A6K2 A6K3 V6K2 V6K3 V6K4 L6K2 L6K3 L6K4 L6K5
nanotubes nanovesicles irregular aggregation nanotubes nanovesicles irregular aggregation nanoribbons nanotubes nanovesicles Irregular aggregation
2.28 7.93 not detected 0.33 0.83 4.65 0.046 0.25 5.38 not detected
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AUTHOR INFORMATION
Corresponding Author
*Phone: 86-10-68169363. Fax: 86-10-68211656. E-mail:
[email protected].
remained constant at approximately 1.5 regardless of concentration, indicating that the pyrene molecules were surrounded by a hydrophilic environment at these concentrations. At higher
Notes
The authors declare no competing financial interest. 5021
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ACKNOWLEDGMENTS This work was supported by The National Key Technologies R&D Program for New Drugs of China (2012ZX09301003).
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