The decoration of a peptide-based artificial viral capsid with gold nanoparticles (AuNPs) is reported. β-Annulus GGGCG-bearing peptide as a binding site of AuNPs self-assembled into nanocapsules with a diameter of 50 nm. The addition of AuNPs to the peptide nanocapsules afforded relatively uncontrolled assemblies of AuNPs. In contrast, the self-assembly of AuNP–peptide conjugates afforded, after dialysis, controlled assemblies of AuNPs with sizes of 30–60 nm. ζ-Potential measurements revealed that the surface of the artificial viral capsid self-assembled from β-annulus peptide was coated with AuNPs.
Fusion materials of gold nanoparticles (AuNPs) and biomacromolecules have attracted much attention because these materials provide versatile tools for use in applications such as catalysis, biosensing and bioimaging systems.1, 2, 3, 4 AuNPs have useful electronic, optical and plasmonic properties, which depend on the diameter of the nanoparticles and the structure of the assemblies. To date, the spatial arrangement of AuNP assemblies has been achieved via the programmed self-assembly of biomacromolecules such as DNA.5, 6, 7, 8, 9, 10, 11, 12, 13 For example, Shultz and colleagues8, 9 demonstrated that oligodeoxyribonucleotide (ODN) conjugates with tethered AuNPs could be arranged by hybridization with the complementary ODN templates. Seeman and colleagues10, 11 reported that a two-dimensional arrangement of AuNPs with nanosized precision was achieved by the self-assembly of double-crossover DNAs.
Natural viral capsids are also attractive biomolecular nanomaterials. Because viral capsids are protein assemblies with a discrete size, space and a specific aggregation number, they have been used as nanoreactors and nanocontainers for inorganic materials, drugs and proteins.14, 15, 16, 17 The surface of viral capsids have been utilized as a scaffold to display biomolecular ligands such as saccharides, DNA aptamers and antigens.14, 15, 16, 17 The regular arrangement of AuNPs on the surface of spherical viral capsids have also been reported.18, 19, 20, 21, 22, 23 Finn and colleagues18 demonstrated that monomaleimide–AuNPs were displayed on the surface of Cys-mutated cowpea mosaic virus with a diameter of 30 nm. Blum et al.19, 20, 21 reported that 5 nm AuNPs were regularly arranged on GGCGG loops inserted into subunit proteins of Cys-mutated cowpea mosaic virus. Niikura et al.22 reported the arrangement of sialic acid-modified AuNPs on JC viral capsids through molecular recognition.
The rational design of self-assembled peptides has been progressively developed for the construction of peptide-based nanoarchitectures.24, 25, 26, 27, 28 The linear arrangement of AuNPs on fibrous assemblies of peptides has also been reported.29, 30, 31 However, the literature contains no reports on the spherical arrangement of AuNPs using a rationally designed peptide assembly as a template. Recently, we demonstrated that the designed 24-mer peptide fragment (INHVGGTGGAIMAPVAVTRQLVGS), which participates in the β-annulus motif in tomato bushy stunt virus, self-assembles into virus-like nanocapsules with sizes of 30–50 nm.32, 33, 34, 35 Herein, we report the construction of an artificial viral capsid decorated with AuNPs, which we examined using the following two methods: (1) modification of the surface of peptide nanocapsules self-assembled from β-annulus-GGGCG peptide 1 (INHVGGTGGAIMAPVAVTRQLVGSGGGCG) with AuNPs and (2) self-assembly of AuNP-β-annulus-GGGCG peptide 1 conjugates (Figure 1).
Materials and methods
Reagents were obtained from commercial sources and used without further purification. A stabilized suspension of AuNPs in citrate buffer (5 nm diameter, 5.5 × 1013 particles ml−1) was purchased from Sigma-Aldrich (St Louis, MO, USA). Reversed-phase high-performance liquid chromatography was performed at an ambient temperature on a Shimadzu LC-6AD liquid chromatograph equipped with a ultraviolet–visible detector (220 nm, Shimadzu SPD-20A) and GL Science Inertsil WP300 C18 (4.6 × 250 mm2 and 20 × 250 mm2) columns. MALDI-TOF (matrix-assisted laser desorption/ionization time-of-flight) mass spectra were obtained on an Autoflex II (Bruker Daltonics, Billerica, MA, USA) spectrometer operated under the linear/positive mode with α-cyano-4-hydroxy cinnamic acid (α-CHCA) as the matrix. Ultraviolet–visible spectra were recorded at 25 °C using a JASCO V-630 spectrophotometer. Circular dichroism spectra were collected in a 1-mm quartz cell with a JASCO J-820 spectrophotometer at 25 °C. Molar concentrations of AuNPs were calculated using the absorbance at 520 nm.
Synthesis of peptide (1)
The peptide H-Ile-Asn(Trt)-His-(Trt)-Val-Gly-Gly-Thr(tBu)-Gly-Gly-Ala-Ile-Met-Ala-Pro-Val-Ala-Val-Thr(tBu)-Arg(pbf)-Gln(Trt)-Leu-Val-Gly-Ser(tBu)-Gly-Gly-Gly-Cys(Trt)-Gly-Alko-PEG resin was synthesized on a Fmoc-Gly-Alko-PEG resin (Watanabe Chemical Industries, Hiroshima, Japan, 0.22 mmol g−1) using Fmoc-based coupling reactions (4 equiv. Fmoc amino acids). Solutions of 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluoro- phosphate (HBTU, 4 equiv.), 1-hydroxybenzotriazole hydrate (HOBt•H2O, 4 equiv.) and diisopropylamine (8 equiv.) in N-methylpyrrolidone were used as coupling reagents. A solution of 20 % piperidine in N,N-dimethylformamide was used for Fmoc deprotection. The progress of the coupling reaction and Fmoc deprotection was confirmed using a TNBS and a Chloranil Test Kit (Tokyo Chemical Industry, Tokyo, Japan). The peptidyl resin was washed with N-methylpyrrolidone.
The peptide was deprotected and cleaved from the resin by treatment with a mixture of trifluoroacetic acid/water/1,2-ethanedithiol/triisopropylsilane=9.5/0.25/0.25/0.1 at room temperature for 3 h. The reaction mixture was filtered to remove the resin and the filtrate was concentrated under vacuum. The peptide was precipitated by the addition of methyl tert-butyl ether to the residue, and the supernatant was decanted. After the peptide was washed with methyl tert-butyl ether three times, the precipitated peptide was dried under vacuum. The crude product was purified by reversed-phase high-performance liquid chromatography (Inertsil WP300 C18), eluting with a linear gradient of CH3CN/water containing 0.1% trifluoroacetic acid (26/74 to 29/71 over 120 min). The fraction containing the desired peptide was lyophilized to give 9.5 mg of a flocculent solid (3 % yield). MALDI-TOF-MS (matrix: α-CHCA): m/z =2638 [M+H]+.
Modification of the surface of peptide nanocapsules with AuNPs
An aqueous solution of β-annulus-GGGCG peptide 1 (0.2 mM, pH 4.6) was prepared by simply dissolving it in deionized water. The formation of spherical assemblies was confirmed by dynamic light scattering (DLS) measurements and transmission electron microscopy (TEM). The aqueous solution of peptide 1 (37.5 μl) was mixed with AuNPs in citrate buffer (5.5 × 1013 particles ml−1, 30 μl) and incubated for 60 min at 25 °C. An aliquot (7.5 μl) of 20 mM thioctic acid solution in ethanol/water (4/1) was added to the mixture of peptide 1 and AuNPs, and the resulting mixture was incubated for 10 min at 25 °C. The final concentrations were [peptide 1]=0.1 mM, [AuNP]=0.2 μM and [thioctic acid]=2 mM (pH of the final solution was 3.7).
Construction of artificial viral capsid decorated with AuNPs by the self-assembly of AuNP–peptide conjugates
An aqueous solution of β-annulus-GGGCG peptide 1 was diluted with water to a concentration of 2 μM, which is less than the critical aggregation concentration. An aliquot (2 ml) of the aqueous solution of peptide 1 (2 μM) was mixed with a diluted AuNPs dispersion ([AuNP]=1 μM, 2 ml) and incubated for 60 min at 25 °C. An aliquot (0.5 ml) of 20 mM thioctic acid solution in ethanol/water (4/1) was added to the mixture of peptide 1 and AuNPs, and the resulting mixture was incubated for 10 min at 25 °C. The water in the mixture was evaporated using a Smart Evaporator (Bio Chromato, Fujisawa, Japan). The residue was redispersed by the addition of water (80 μl) to final concentrations of [peptide 1]=50 μM and [AuNP]=25 μM. To remove the unassembled AuNPs, peptides and AuNP–peptide conjugates, the dispersion of AuNP–peptide conjugates was dialyzed to equilibrium against water using Spectra/Por dialysis tubing (cutoff Mw=50 kDa, Spectrum Laboratories, Rancho Dominguez, CA, USA). Nanostructures of the assemblies were evaluated by DLS measurements and TEM observations.
DLS measurements were performed using a Zetasizer NanoZS (MALVERN Instruments, Worcestershire, UK) instrument at 25 °C with an incident He–Ne laser (633 nm). During the measurements, the count rate (the sample-scattering intensity) was also provided. The correlation time for the scattered light intensity G(τ) was measured several times, and the averaged results were fitted to equation 1:
where B is the baseline, A is the amplitude, q is the scattering vector, τ is the delay time and D is the diffusion coefficient. The hydrodynamic radius (RH) of the scattering particles was calculated using the Stokes–Einstein equation (equation 2):
where η is the solvent viscosity, kB is Boltzmann’s constant and T denotes the absolute temperature.
We determined the ζ-potential of peptide assemblies at pH 4.6 by measuring the electrophoretic mobility at 25 °C in disposable Zeta cells using a Zetasizer NanoZS (MALVERN Instruments, Ltd).
Transmission electron microscopy
An aliquot (5 μl) of each sample solution was applied to a carbon-coated grid (ALLIANCE Biosystems, Osaka, Japan), left for 60 s and then removed. The grid was subsequently dried in vacuo. In the case of peptide samples, a drop of 2 wt% aqueous sodium phosphotungstate was placed on each of the grids. AuNPs were observed without the use of a stain. After the sample-loaded carbon-coated grids were dried in vacuo, they were observed by TEM (JEOL JEM 1400 Plus) using an acceleration voltage of 80 kV.
Results and Discussion
29-mer β-annulus-GGGCG peptide 1 (INHVGGTGGAIMAPVAVTRQLVGS GGGCG) was synthesized using the Fmoc-protected solid-phase method, purified by reversed-phase high-performance liquid chromatography and confirmed by MALDI-TOF-MS (m/z =2637 [M]+). The circular dichroism spectrum of the aqueous solution of peptide 1 showed a negative peak at 202 nm and a negative shoulder at approximately 220–230 nm (Figure 2a), which is similar to the circular dichroism spectrum of a 24-mer β-annulus peptide reported previously,32 indicating the coexistence of random-coil, β-sheet and turn structures. DLS measurement of the aqueous solution of peptide 1 showed that peptide 1 formed assemblies with a hydrodynamic diameter of 51±15 nm (Figure 2b). TEM observation of the assemblies stained with sodium phosphotungstate also showed the formation of spherical structures with a diameter of approximately 50 nm (Figure 2c), which is comparable to the size (30–50 nm) of nanocapsules self-assembled from 24-mer β-annulus peptide.32 The concentration dependence of peptide 1 on the scattering intensity (DLS count rate) revealed that the critical aggregation concentration at 25 °C is 29 μM, which is comparable to the critical aggregation concentration (25 μM) of 24-mer β-annulus peptide under the same conditions.32 These results indicate that the addition of GGGCG to the terminus of the β-annulus peptide minimally affected the size, morphology and stability of the spherical peptide assemblies.
To construct artificial viral capsids decorated with AuNPs, an aqueous dispersion of AuNPs was added to the aqueous dispersion of nanocapsules self-assembled from β-annulus-GGGCG peptide 1, and then the surface of the AuNPs was subsequently protected with thioctic acid to prevent further aggregation (Figure 1a). When a suspension of 0.2 μM AuNPs was mixed with 0.1 mM peptide 1, the TEM micrographs of the product showed the formation of spherical assemblies with a diameter of 10–50 nm and which comprised 2–40 AuNPs with a diameter of 5 nm (Figure 3a). In contrast, the TEM micrographs of AuNPs in the absence of peptide 1 showed only individually dispersed AuNPs (Supplementary Figure S1). The DLS of the mixture of AuNPs and peptide 1 also showed the formation of assemblies with a hydrodynamic diameter of 60±19 nm (Figure 3b). The ultraviolet–visible spectrum of AuNPs in the presence of the peptide nanocapsule was slightly red-shifted (Figure 3c), which is ascribed to plasmon coupling among AuNPs self-assembled on the peptide nanocapsule. Notably, assemblies of AuNPs were observed, although the concentration of AuNPs was remarkably smaller than that of peptide 1. Niikura et al.22 reported the cooperative binding of sialic-acid-modified AuNPs on JC viral capsid. In the present study, the AuNPs apparently cooperatively adsorbed onto Cys residues at the surface of the peptide nanocapsules. However, the assemblies consisting of several AuNPs were also observed in the TEM micrographs (Figure 3a); therefore, controlling the aggregation number of AuNPs on a peptide nanocapsule is difficult with this method.
Next we examined the construction of artificial viral capsid decorated with AuNPs by the self-assembly of AuNP–peptide 1 conjugates (Figure 1b). We mixed AuNPs with a diluted solution of β-annulus-GGGCG peptide 1 at a concentration below the critical aggregation concentration to prepare their conjugate and then protected the surface of the AuNPs with thioctic acid. The solvent in the dispersion of conjugate was evaporated, and the conjugate was subsequently redispersed in water to final concentrations of [peptide 1]=50 μM and [AuNP]=25 μM. The TEM images of the dispersion of AuNP–peptide 1 conjugates showed the coexistence of AuNP assemblies with a diameter of 30–50 nm and unassembled AuNPs (Figure 4a). After the unassembled AuNPs were removed using a dialysis membrane (cutoff Mw =50 kDa), AuNP assemblies with diameters of 30–60 nm were selectively observed in the TEM images (Figure 4b). The DLS of the dialyzed dispersion of AuNP–peptide 1 conjugates also indicated the formation of assemblies with a hydrodynamic diameter of 76±25 nm (Figure 4b). The assemblies observed by TEM consisted of 22–63 AuNPs, which partially corresponds to the ideal aggregation number of 60 for a dodecahedral peptide assembly. The increase in diameter compared with that of unmodified peptide nanocapsules (51±15 nm, Figure 2b) suggests that AuNPs decorate the surface of the peptide nanocapsules. The ultraviolet–visible spectrum of the assembly of AuNP–peptide 1 conjugates was approximately the same as that of individual AuNPs (Figure 4c), which indicates that the AuNPs are separated from one another on the peptide nanocapsules. The difference between hydrodynamic diameters obtained from DLS before and after dialysis (Figures 4a and b) might be caused by pH change of the solutions (The pH before dialysis was 3.7, but that after dialysis was 4.6).
As previously reported,34 the pH dependence of the ζ-potential of peptide nanocapsules self-assembled from β-annulus peptide indicates that the C termini are directed toward the exterior of the peptide nanocapsules. Therefore, we expected that Cys residues of β-annulus-GGGCG peptide 1 and AuNPs are directed toward the exterior of the peptide nanocapsules. The ζ-potential of unmodified peptide nanocapsules was approximately neutral (0.01±3.43 mV) at pH 4.6 (Figure 5a). In contrast, the ζ-potential of the assemblies of AuNP–peptide 1 conjugates was −30.5±9.8 mV at pH 4.6 (Figure 5b), corresponding to that of AuNP dispersion in citrate buffer (−30.0±12 mV, Supplementary Figure S1). These results clearly indicate that the surface of artificial viral capsid self-assembled from β-annulus peptide was coated with AuNPs.
We demonstrated that AuNP (5 nm)-β-annulus-GGGCG peptide self-assembled to afford artificial viral capsids decorated with AuNPs. The AuNP-modified viral capsids could be applied as scattering imaging capsules in cells.36 The present strategy extends the design of artificial viral capsids to include decoration with other functional molecules such as proteins, DNA and fluorophores.
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This research was partially supported by a Grant-in-Aid for Scientific Research on the Innovative Areas of ‘Fusion Materials’ (No. 2206) from the Ministry of Education, Science, Sports and Culture of Japan (MEXT) and by the Asahi Glass Foundation.
Supplementary Information accompanies the paper on Polymer Journal website
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Matsuura, K., Ueno, G. & Fujita, S. Self-assembled artificial viral capsid decorated with gold nanoparticles. Polym J 47, 146–151 (2015). https://doi.org/10.1038/pj.2014.99