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Structural Transition in Peptide Nanotubes Nadav Amdursky,†,# Peter Beker,‡,# Itai Koren,‡ Becky Bank-Srour,‡ Elena Mishina,§ Sergey Semin,§ Theo Rasing,|| Yuri Rosenberg,^ Zahava Barkay,^ Ehud Gazit,† and Gil Rosenman*,‡ †
)
Department of Molecular Microbiology and Biotechnology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel ‡ School of Electrical Engineering, Iby and Aladar Fleischman Faculty of Engineering, Tel Aviv University, Tel Aviv 69978, Israel § Moscow State Institute of Radioengineering, Electronics and Automation, Prospect Vernadskogo 78, 119454 Moscow, Russia Institute for Molecules and Materials, Radboud University, Heijendaalseweg 135, 6525 AJ Nijmegen, The Netherlands ^ Wolfson Applied Materials Research Center, Tel Aviv University, Tel Aviv 69978, Israel
bS Supporting Information ABSTRACT: Phase transitions in organic and inorganic materials are well-studied classical phenomena, where a change in the crystal space group symmetry induces a wide variation of physical properties, permitted by the crystalline symmetry in each phase. Here we observe a conformational induced transition in bioinspired peptide nanotubes (PNTs). We found that the PNTs change their original molecular assembly from a linear peptide conformation to a cyclic one, followed by a change of the nanocrystalline structure from a noncentrosymmetric hexagonal space group to a centrosymmetric orthorhombic space group. The observed transition is irreversible and induces a profound variation in the PNTs properties, from the microscopic to the macroscopic level. In this context, we follow the unique changes in the molecular, morphological, piezoelectric, second harmonic generation, and wettability properties of the PNTs.
’ INTRODUCTION Classic structural phase transitions in organic and inorganic crystals are generally described by small atomic displacements, where each phase is characterized by a specific space group, which unambiguously defines its physical properties.1 7 Contrary to the common models of structural phase transitions, such as ferroelectric phase transitions described by the Landau Ginzburg Devonshire theory,3 the phenomenon of a chemical conformational induced transition is very common in organic and biologic complexes. Such conformational transition results from variations at the molecular level8 12 and often leads to dramatic variation of molecular crystals symmetry.13 The molecular transformation may involve strong covalent bonds, or weak noncovalent interactions like hydrogen bonds, van der Waals, hydrophobic, aromatic, and π-stacking interactions. Due to energy considerations, the covalent related conformational transitions are usually irreversible, whereas the noncovalent related transition is usually reversible.14,15 One of the molecular transformations that involve covalent bonding is the irreversible formation of diketopiperazine from small peptides, as in the following work.16 18 Diketopiperazines are known to have biological activity as physiological inhibitors.16 The conventional synthesis procedures of diketopiperazines are solid-phase techniques that involve the use of resin, protecting groups and protein cleavage.16,19 r 2011 American Chemical Society
In this work we studied the conformational induced phase transition of peptide nanotubes (PNTs) that self-assemble from two phenylalanine residues (diphenylalanine (FF), NH2 Phe Phe COOH). This short peptide, which was inspired by the core recognition motif of the Alzheimer’s disease, can self-assemble in an aqueous solution to a rigid PNT20 with a pronounced nanocrystalline structure of 6-fold crystallographic hexagonal symmetry.21,22 The optical properties of the resulting self-assembled peptide structures reveal an exceptional quantum confinement phenomenon, which results from the presence of nanocrystalline periodic arrangements in the order of a few nanometers.23 26 The nanocrystalline structure of PNT, in addition to its hexagonal noncentrosymmetric space group,21 has encouraged us to explore its electromechanical properties. We found anomalously strong shear piezoelectric activity with effective piezoelectric coefficient values of at least 60 pm/V.27 Recently, we reported that the same small FF peptide can undergo a different self-assembly process in physical vapor deposition (PVD), which yields uniform dense arrays of vertically aligned PNTs.28 Even though we use the same FF peptide building block, the morphological, molecular, optical, and Received: January 25, 2011 Revised: March 10, 2011 Published: March 10, 2011 1349
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Figure 1. Molecular transition. (A) ToF-SIMS analysis of the PNT native phase. The inset shows the molecular diagram of the linear-FF molecule. (B) ToF-SIMS analysis of the PNT thermal induced phase. The inset shows the molecular diagram of the cyclic-FF molecule. (C) TGA analysis of PNTs.
Table 1. XPS Analysis of Both the Native Phase and the Thermal Induced Phase of PNT, along with the Theoretical Ratios of the Linear-FF and the Cyclic-FF Molecules atomic ratio
linear structure theoretical value
native phase experimental value
cyclic structure theoretical value
thermal induced phase experimental value
C:O
18:3 = 6:1
6.4:1
18:2 = 9:1
8.40:1
C:N N:O
18:2 = 9:1 2:3 = 0.67:1
8.92:1 0.73:1
18:2 = 9:1 2:2 = 1:1
8.95:1 0.95:1
electronic properties of the PVD formed PNTs are completely different from the properties of the PNTs formed in an aqueous solution. Unlike the latter, the PVD formed PNTs are much narrower and sometimes look like rods or belts. They exhibit an exceptional blue luminescence,25 compared to the UV luminescence of the PNTs formed in aqueous solution.24 Their final structure is composed from cyclic-FF,28 rather than the initial linear peptide. The most likely cause for the large differences between these two PNT structures is the involvement of heating during the PVD process. This assumption is also supported by the work of Ryu and Park,29 who observed the formation of peptide nanowires, which resemble our PVD formed PNTs, by using anhydrous conditions and exposure to aniline vapor at 150 C. In this study we have compared the properties of PNTs that were formed in an aqueous solution at their native phase, and the same PNTs following a thermal treatment at 150 C. The study spans the whole range from the elementary molecular level, which influences their morphology, through their XRD, structural, piezoelectric, and optical second harmonic generation (SHG) properties, which strongly vary at the level of a single tube, up and until their macroscopic wettability properties that characterize a bundle of tubes.
’ EXPERIMENTAL METHODS PNTs Preparation. Fresh stock solutions of diphenylalanine (FF) were prepared by dissolving the FF peptide in lyophilized form in 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) at a concentration of 100 mg/mL.
The stock solution was diluted to a final concentration of ∼2 mg mL 1 in ddH2O for nanotubes creation. We refer to those PNTs as native phase PNTs. The thermally induced PNTs were formed by drying the native phase PNTs on a given surface, followed by heating at 150 C for 30 min.
Scanning Transmission Electron Microscope (STEM) Measurements. The samples were investigated in FEI Quanta 200 FEG
environmental scanning electron microscope (ESEM) using simultaneously the Everhart Thornley (ET) secondary electron detector and the STEM detector at a primary beam energy of 20 keV. The STEM detector is a two segment planar solid-state p n junction device attached underneath the grid holder assembly. The two detector segments can be switched independently, enabling the possibility of bright field and dark field contrast modes. The quick ET detector response provides inspection at a TV scan while navigating in the sample, while STEM imaging is obtained at a longer scan time of typically 20 s per frame after choosing the inspection region. X-ray Diffraction (XRD). The normalized XRD patterns were obtained in symmetrical Bragg geometry with Cu KR radiation on Θ Θ powder diffractometer Scintag equipped with a liquid nitrogen cooled Ge solid-state detector. Piezo Force Microscopy (PFM) Images. The PNT were deposited on gold surfaces (Si wafer, 15 nm Cr, 300 nm Au) or platinum surfaces (Si wafer, 150 nm Pt). The PFM images were obtained with a Digital Instrument (DI) MultiMode NanoScope IV AFM, by using an external function generator and lock-in amplifier. Thermal Gravimetric Analysis (TGA). TGA of the PNT native phase was conducted using a TA 2050 TGA analyzer. The sample was heated under air atmosphere at a heating rate of 8 C/min. 1350
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conformation are stretch = 134.3236 kcal mol 1, bend = 5.3636 kcal mol 1, stretch bend = 3.3837 kcal mol 1, torsion = 7.3016 kcal mol 1, non van der Waals = 8.2404 kcal mol 1, van der Waals = 0.9498 kcal mol 1, dipole/dipole = 4.4764 kcal mol 1, which yield a total energy of 117.2349 kcal mol 1.
Figure 2. Morphological transition. (A) STEM image of a native phase PNT, which exhibits its central hole. (B) A higher magnification of the PNT. In this stage, the PNT is being heated by the electron beam. (C) The same location as (B) after a few seconds. (D) A lower magnification of the same PNT, where the difference between the thermal induced phase and the native phase can be clearly seen. (E H) ESEM images of a PNT tip while heating with the electron beam at t = 0, 10, 15, 20 s, respectively. The scale bar in (E) is 2 μm and it is valid to (E H). (I) ESEM image of vertically aligned PNTs prior to the heating. (J) ESEM image of vertically aligned PNTs after the heating. The scale bar is 20 μm for (I) and (J).
X-ray Photoelectron Spectroscopy (XPS). XPS measurements were conducted using a 5600 Multi-Technique System (PHI). The samples were irradiated with an Al KR monochromated source, and the outcome electrons were analyzed by a hemispherical analyzer. Second Harmonic Generation (SHG) Measurements. A 100 fs laser (MaiTai, NewPort-SpectraPhysics) with high pulse power density was used, using a chopper 1/10 for cooling. Radiation in the UV and visible ranges was detected with a high spectral resolution tool, by using SpectraPro monochromator and CCD (Princeton Instrument). Wettability Measurements. High resolution wettability studies were performed using ESEM. The measurements were made with Quanta 200 FEG ESEM in Wet-mode. By manipulating the pressure and temperature within the ESEM chamber, using a Peltier cooling stage, it is possible to induce the condensation and evaporation of aqueous fluids. By this method we were able to follow the dynamic properties of the PNT wetting process. Energy Calculations. The linear and the cyclic conformations of the diphenylalanine peptide were energy minimized by using an MM2 force field. The calculated energies for the linear peptide conformation are stretch = 294.0888 kcal mol 1, bend = 6.7326 kcal mol 1, stretch bend = 5.4231 kcal mol 1, torsion = 12.7924 kcal mol 1, non van der Waals = 8.6256 kcal mol 1, van der Waals = 3.3398 kcal mol 1, dipole/dipole = 2.1022 kcal mol 1, which yields a total energy of 275.2179 kcal mol 1. The calculated energies for the cyclic peptide
’ RESULTS AND DISCUSSION Figure 1 shows the structural molecular transition of the same PNTs before and after the thermal treatment. The time-of-flight secondary ion mass spectrometry (ToF-SIMS) analysis describes the thermally induced molecular transition by altering the molecular weight of the structure from 313 g 3 mole 1 (Figure 1a), corresponding to the linear form of the diphenylalanine peptide, to 295 g 3 mol 1 (Figure 1b), corresponding to the cyclic form of the peptide (the schemes of the linear and cyclic peptides are displayed in the insets of Figure 1a,b, respectively). To validate this molecular transition, from linear peptide to a diketopiperazine cyclic peptide, we measured the ratios between the carbon, nitrogen, and oxygen atoms of the PNTs, before and after the thermal treatment via X-ray photoelectron spectroscopy (XPS) (Table 1) . During the cyclization process, the peptide loses an H2O molecule (which corresponds to the difference in the observed molecular weight); hence the ratios of carbon and nitrogen with oxygen should change during the molecular transition. Indeed, the observed atomic ratios fit to the theoretical values of the linear and cyclic peptide before and after the heat treatment, respectively. (The XPS patterns for carbon, nitrogen and oxygen are displayed in Figure S1 in the Supporting Information.) The conformational induced phase transition point can be clearly seen at the thermal gravimetric analysis (TGA) of the PNTs (Figure 1c), in which a step is located around 150 C. Figure 2a shows a scanning transmission electron microscope (STEM) image of a single PNT before the thermal treatment (in its native phase) with a central hole of 120 nm. When we focus the electron beam on the tube (Figure 2b), we start to heat the tube, and within seconds the tube morphology is changed, reflected by the disappearance of the central hole, and the PNT transforms into a peptide nanofiber (PNF) structure (Figure 2c). This is in agreement with the observed morphology of the PNTs grown by PVD.28 At a lower magnification we can see the difference between the thermally induced part (on the left) and the original part (on the right) of the tube (Figure 2d). The exposure with a 30 KeV e-beam of typically 6 10 2 C cm 2 electron dosage caused a shrinkage of about 15% in diameter (from 380 to 320 nm) and a correspondingly 30% volume reduction. In a fast evaporation process from aqueous solution, the selfassembled native PNTs align perpendicularly to the surface. In this way, we could follow the morphological transition, i.e., the closing of the PNT, due to the heating by the e-beam radiation from above (see Figure 2e h and the movie in the Supporting Information). The native open-end PNT has pronounced hexagon faceting, which is gradually closing and thus changing its cross section to a shapeless one. During the electron beam radiation, the heating process is highly local and we observe the beginning of the conformational change, where the central hole of the tube is closing. The crystal model of the PNT in its native phase30 suggests a representation for the inner surface of the nanotubes, containing multiple hydrophilic/hydrophobic channels. In addition to the closing of the central hole, the 1351
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Figure 3. XRD patterns of native phase PNTs (blue lower curve) and thermal induced PNTs (red upper curve).
multiple channels network is also closing (which affects the wettability properties of the PNTs, as will be discussed later). The closing of the multiple channels networks splits the tube into several low diameter needles, thus the morphology of the structures at their native and thermally induced phases (after applying an external heat of around 160 C for 2 h) is completely different (Figure 2i,j, respectively). The molecular and morphological transitions are accompanied by a change in the crystal structure of the tubes. The normalized X-ray diffraction (XRD) patterns are shown in Figure 3. The lower blue pattern of the native PNT fits well the hexagonal structure of the phenylalanine dipeptide (space group P61), which was previously determined by single crystal XRD.21 According to its XRD pattern, the structure of the thermally induced PNT phase (upper curve) differs essentially from the native one, while the XRD patterns of thermally induced PNF and powder of structures that are made from cyclo-FF dipeptides are very similar (Figure S2, Supporting Information). Although an unambiguous indexing of the XRD pattern of the thermally induced PNF was not achieved, it was found that the most likely unit cells that could account for all the observable Bragg reflections tend to be orthorhombic, with the hit list sorted on the figure of merit starting with Pbca, Pnma, Pbam, and Pbcn space groups. It is important to note that all these space groups are centrosymmetric. The Miller indices (hkl) assignments in Figure 3 correspond to the orthorhombic unit cell (Pbca: a = 10.31, b = 8.42, and c = 23.87 Å) for the thermally induced PNF and the hexagonal unit cell (P61: a = b = 24.15 and c = 5.46 Å) for native PNT. The phase transition of the PNTs, from a noncentrosymmetric space group to a centrosymmetric one is directly related to the piezoelectrical properties of the material. PNTs with a noncentrosymmetric P61 space group show a strong longitudinal piezoelectric signal.27 The transition from a noncentrosymmetric space group to a centrosymmetric one should eliminate the piezoelectric characteristic of the PNT. We followed the biasdependent piezoelectric signal of the PNT at both of the phases by piezoelectric force microscopy (PFM) (Figure 4a). Whereas the native PNT exhibits a linear bias-dependent piezoelectric signal, the thermally induced PNF (The same tube as was measured for the native phase) does not exhibit any piezoelectric signal. (The PFM images of the native and thermally induced PNT and PNF are displayed in Figure S3a,b, respectively, Supporting Information.) An additional characteristic, which is also directly related to the absence of centrosymmetry, is optical second harmonic
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generation (SHG). The native noncentrosymmetric phase should exhibit SHG, whereas the thermally induced centrosymmetric phase should not. Figure 4b shows the emission spectrum of the PNTs, following optical excitation with a wavelength of λpump = 800 nm, of the native and thermally induced phase (red and black curves, respectively). The pronounced SHG peak clearly seen for the native phase PNT, disappears for the thermally induced phase. The SHG nature of the optical response of the tubes was further validated by measuring its intensity as a function of the pump laser power (Inset of Figure 4b), showing indeed a quadratic dependence. Figure S4 (Supporting Information) shows the SHG luminescence of the PNTs, with an intense luminescence at the spot of the laser, and the corresponding emission spectrum within this spot, which indicates that the luminescence is the SHG one. The structural phase transition also affects the macroscopic wettability characteristics of a bundle of PNTs. As mentioned previously, the crystal model of PNT in its native phase30 suggests a representation for the inner surface of the nanotubes, containing multiple hydrophilic/hydrophobic channels, aligned parallel to the main axis of the tube (See Figure 3 in ref 30). The alignment of the multiple channels causes the PNT to be hydrophilic in nature. As discussed previously, the thermally induced phase loses this structure and does not exhibit this multiple channel alignment. Accordingly, we would expect, in agreement with our previously reported results on the PVD formed peptide structures,31 that the thermally induced PNFs will be highly hydrophobic. High resolution environmental scanning electron microscope (ESEM) measurements allowed us to observe in details the wetting dynamics of bundles of PNTs.32 At the beginning of the ESEM experiment the sample was stabilized at 2 C while the pressure in the chamber was held at 5 Torr to avoid vapor condensation. The pressure was increased at an approximate rate of 0.1 Torr for every 30 s. Since condensation of water within the ESEM chamber occurs suddenly, this slow pressure increase rate allows a better control of liquid formation. While examining the wetting dynamics of bundles of PNTs at the native phase (Figure 5a,b), we observed a rapid full wetting of the PNTs bundles at 5.9 Torr (a high magnification of wetting process can be seen in the movie in the Supporting Information), which can be explained by the hydrophilic nature of this native phase. In contrast, the hydrophobic nature of the thermally induced PNF phase dictates a completely different wettability behavior, as demonstrated by the repelling of water in Figure 5c,d. We can also spot several nucleation points of water droplets on the PNFs surface, which exhibit a hydrophobic contact angle and do not soak into the PNFs, as in the case of the native phase bundles (marked with arrows at Figure 5c). All of the described transitions are irreversible, meaning that following the thermal treatment, the new molecular, morphological, piezoelectric, and optical properties are stable at their current state. As in common diketopiperazines, the irreversibility is due to the cyclization process undergone by the linear-FF peptide. During this process, the amino and the carboxylic ends of the peptide are being connected via a covalent bond, while a water molecule is released. The irreversibility of this process can be also explained by energy considerations. The thermally induced phase composed of cyclic-FF, is more stable than the native phase composed of linear-FF by ΔE = 157.983 kcal mol 1 (275.218 and 117.235 kcal mol 1 for the linear-FF and cyclic-FF conformation, respectively). (The detailed energy composition is given in the Experimental Methods.) 1352
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Figure 4. Piezoelectrical and SHG phase transition. (A) Piezoelectric response as a function of the applied bias of the native phase (red curve), which exhibits linear dependence, and of the thermal induced phase (black curve), which does not exhibit a piezoelectric signal. (B) Emission spectrum, following the excitation wavelength of λpump = 800 nm, of the native and thermally induced phase (red and black curves, respectively). The inset shows the emission intensity of the signal, as a function of the pumping laser power.
Figure 5. Wettability properties. (A) ESEM image (at wet mode) of a bundle of PNTs at the native phase, showing a completely wetted surface. (B) A higher magnification of the surface during the wetting process. (C) ESEM image of a bundle of PNTs at the thermal induced phase, showing the hydrophobic nature of the surface. (D) A higher magnification of two droplets on the surface, showing the hydrophobic contact angle of the droplets.
All the observed experimental results are consistent with thermally induced multiple transitions. The conformational transition (Figure 1), which occurs due to the cyclization process of the molecule, from a linear peptide to a diketopiperazine cyclic peptide, induces a transition in the XRD pattern of the PNTs (Figure 3). The transition between noncentrosymmetric to centrosymmetric crystal structure allows us to consider this transition as a phase transition. As in common phase transition,
the transition is accompanied by changes in the piezoelectric and SHG properties of the PNTs (Figure 4a,b, respectively).
’ CONCLUSION In conclusion, we have shown that a thermally induced phase transition of self-assembled PNTs leads to substantial changes in their structure and properties, from the molecular level up and 1353
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Biomacromolecules until the macroscopic level. The two phases have different crystalline symmetries and have completely different properties. The native PNT has a noncentrosymmetric structure, composed of linear-FF molecules. This noncentrosymmetric structure possesses both a high piezoelectric coefficient and strong optical nonlinearity (SHG). The macroscopic morphology of this native phase PNT shows pronounced crystallographic faceting with each individual PNT having a hexagonal shape, consistent with its crystallographic hexagonal symmetry. Moreover, these structures are highly hydrophilic. Above the phase transition, the thermally induced PNF has a centrosymmetric structure, composed of diketopiperazine cyclic-FF molecules. The phase transition to the centrosymmetric structure results in a total disappearance of the piezoelectric and SHG signals. The lack of any crystallographic faceting in its macroscopic morphology is consistent with the suggested orthorhombic centrosymmetric structure. These centrosymmetric PNFs are completely hydrophobic. Both phases have a high potential for applications, where the native phase may be used for piezoelectric and nonlinear optical conversion devices, and the thermally induced phase for hydrophobic biosurfaces.
’ ASSOCIATED CONTENT
bS
Supporting Information. Figures S1 S4 (XPS and XRD patterns; AFM and PFM images; SHG image) and movies. This material is available free of charge via the Internet at http:// pubs.acs.org.
’ AUTHOR INFORMATION Corresponding Author
*E-mail:
[email protected]. Author Contributions #
These authors contributed equally to this work.
’ ACKNOWLEDGMENT We thank Prof. D. Huppert for the helpful discussions and for the assistance with the photoluminescence measurements. Thanks are also to A. Daikich for the ToF-SIMS analysis, L. Burstein for the XPS analysis, and A. van Etteger for the SHG images. N.A. thanks the clore scholars program for financial support. P.B. thanks the “converging technologies” program of the council for higher education for financial support. Part of this work was supported by the EU FP7 programme HIERARCHY and the Dutch Organisation for Scientific Research (NWO).
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