Article pubs.acs.org/Langmuir
A Capped Dipeptide Which Simultaneously Exhibits Gelation and Crystallization Behavior Adam D. Martin,*,†,‡ Jonathan P. Wojciechowski,†,‡ Mohan M. Bhadbhade,†,§ and Pall Thordarson*,†,‡ †
School of Chemistry, ‡The Australian Centre for Nanomedicine and the ARC Centre of Excellence for Convergent Bio-Nano Science and Technology, and §Mark Wainwright Analytical Centre, The University of New South Wales, Sydney, 2052 NSW, Australia S Supporting Information *
ABSTRACT: Short peptides capped at their N-terminus are often highly efficient gelators, yet notoriously difficult to crystallize. This is due to strong unidirectional interactions within fibers, resulting in structure propagation only along one direction. Here, we synthesize the N-capped dipeptide, benzimidazolediphenylalanine, which forms both hydrogels and single crystals. Even more remarkably, we show using atomic force microscopy the coexistence of these two distinct phases. We then use powder X-ray diffraction to investigate whether the single crystal structure can be extrapolated to the molecular arrangement within the hydrogel. The results suggest parallel β-sheet arrangement as the dominant structural motif, challenging existing models for gelation of short peptides, and providing new directions for the future rational design of short peptide gelators.
■
INTRODUCTION Low molecular weight gelators (LWMGs) have recently enjoyed a rapid increase in popularity, due to potential applications in drug delivery, as extracellular matrix mimics and as functional materials.1−4 One subdiscipline of this field involves using short peptides to form supramolecular hydrogels. The use of peptides offers advantages in tunability, as peptide sequences which mimic biological functions such as RGD and IKVAV can be used;5−7 however, for short peptides to form robust hydrogels, often an aromatic capping group is employed at the N-terminus of the peptide.8−10 This capping group can be a standard Fmoc moiety used in solid phase peptide synthesis or something more functional, like a capping group which provides photoswitching or hydrogen bonding capabilities.11,12 Gels have previously been described as frustrated crystallizations, as within gels there is some degree of order, as seen by circular dichroism, but not enough periodic order for crystallization or powder X-ray diffraction studies. Gels often exhibit strong unidirectional interactions, which allows for onedimensional gel fibers to form; however, this prohibits the determination of crystal structures of these materials, especially for short peptide hydrogelators. Phase changes within short peptide hydrogels have been known to occur,13 however only a couple of examples of crystal structures of N-terminal capped short peptides exist,14,15 and in both cases the packing of the molecules in the crystal structure is different to packing in the gel. In this work, we report a new capped dipeptide, benzimidazole-diphenylalanine, which in addition to forming © XXXX American Chemical Society
a hydrogel via a pH switching method also forms single crystals. Hirshfeld surface analysis shows the prominent interactions present in the crystal structure and atomic force microscopy imaging remarkably shows the coexistence of both a crystalline and gel state. Powder X-ray diffraction studies confirm that the structure of the xerogel is related to that of the single crystal, whereas the native gel displays significantly more amorphous character.
■
EXPERIMENTAL SECTION
Benzimidazole acetic acid was synthesized in two steps from benzimidazole, which was first alkylated using K2CO3 and tert-butyl bromoacetate, before hydrolysis was performed with trifluoroacetic acid (Scheme 1). The peptide was synthesized using solid phase peptide synthesis,16 employing HOBt/HBTU as the coupling reagents. Benzimidazole acetic acid was coupled to the diphenylalanine peptide in this manner; however a double coupling procedure was required. Full experimental details including yields and characterization can be found in the Supporting Information. All chemicals and solvents used were purchased from Sigma-Aldrich or ChemImpex and used as supplied.
■
RESULTS AND DISCUSSION Synthesis and Gel Characterization. After solid phase peptide synthesis and purification by semipreparative HPLC, the peptide was obtained in 38% overall yield (Scheme 1). Gelation tests revealed that benzimidazole-diphenylalanine Received: October 27, 2015 Revised: January 12, 2016
A
DOI: 10.1021/acs.langmuir.5b03963 Langmuir XXXX, XXX, XXX−XXX
Article
Langmuir
benzimidazole-diphenylalanine (Figure S6) show minimal differences in peak positions and intensities, suggesting no major structural rearrangement upon crystallization. Rheological measurements were performed to assess the strength of the hydrogel. These measurements took place at a gelator concentration of 1% (w/v), with hydrogels formed via a pH switch method with GdL. It can be seen that the storage modulus of the hydrogel is independent of frequency, with the strength of the gel, 5.5 kPa, comparable to that of other reported short peptide hydrogels (Figure 1c).19−21 The strain sweep shows that the gel is quite malleable, with the linear viscoelastic region persisting until almost 10%, before failure occurs at 60% strain (Figure 1d). These values suggest that these gels are able to withstand a moderate amount of oscillatory strain before any irreversible deformation effects are seen. This may be due to the coexistence of fibers and crystallites within the hydrogel, and will be discussed in more detail later. Crystal Structure of Benzimidazole-Diphenylalanine. Single crystals of benzimidazole-diphenylalanine were obtained from slow evaporation of a saturated solution in a 3:2 mixture of acetonitrile/acidic (pH 4) water. Crystals were obtained as transparent needles and crystallized in the space group P21, with one molecule in the asymmetric unit (Figure 2a).
Scheme 1. Synthesis of Benzimidazole Acetic Acid Capping Group and Benzimidazole-Diphenylalanine
formed gels via pH switch only using glucono-δ-lactone17 (not heat cooling in PBS or solvent switch using DMSO and DMEM, like some of our previous hydrogels)10 and that gels were formed down to a concentration of 0.1% (w/v). Circular dichroism studies reveal a negative peak at 216 nm (Figure 1a), which indicates the formation of a β-sheet
Figure 2. (a) Asymmetric unit of benzimidazole-diphenylalanine (a), crystal packing diagram as viewed down the a axis (b), hydrogen bonding between adjacent amides (c), and double interaction between the C-terminal carboxylate and the benzimidazole capping group (d).
Interestingly, no solvent molecules are present in the structure, suggesting strong intermolecular interactions. This is consistent with previous molecular modeling studies performed on Fmocdialanine fibrils where water was found to be expelled from the fibrils upon self-assembly.22 This lack of solvent molecules is also observed in a Fmoc-4-nitrophenylalanine, which crystallizes after an initial phase of gelation.23 There are two main structure directing interactions in the crystal structure, with one being the β-sheet motif which runs down the a axis (Figure 2c). Interestingly, the β-sheets adopt a parallel arrangement, similar to that observed in the crystal structure of Fmoc-diphenylalanine (Fmoc-FF),14 presumably due to steric factors associated with the aromatic phenylalanine and benzimidazole moieties. This parallel β-sheet structure is contrary to currently accepted models of self-assembly within short peptides via antiparallel β-sheets, and such a parallel βsheet arrangement is confirmed by obtaining values of
Figure 1. Circular dichroism of a benzimidazole-diphenylalanine hydrogel prepared at 1% (w/v) followed by a 1:8 dilution with Milli-Q water (a), ATR-IR of a benzimidazole-diphenylalanine hydrogel at 1% (w/v) in D2O, amide I region (b), frequency (c), and strain sweep (d) of 1% (w/v) gels of benzimidazole-diphenylalanine, performed at 25 °C.
secondary structure, which is common for peptides bearing diphenylalanine moieties. This β-sheet character was confirmed further by ATR-IR, which was performed in D2O and showed a peak at 1629 cm−1 (Figure 1b). The additional peak at 1590 cm−1 has previously been ascribed to small number of deprotonated terminal carboxylic acids.18 In order to avoid any interference from the pH switching agent, glucono-δlactone (GdL), CD and ATR-IR studies were performed using gels that had been triggered by HCl. Comparison of the ATRIR spectrum of the hydrogel and crystals obtained for B
DOI: 10.1021/acs.langmuir.5b03963 Langmuir XXXX, XXX, XXX−XXX
Article
Langmuir −114.90° and 99.07° for the dihedral angles φ and ψ within this peptide. When plotted on a Ramachandran plot, this strongly indicates a parallel β-sheet. The second, and more unexpected, structure directing interaction is a bidentate interaction between the benzimidazole capping group and the C-terminus of the amino acid (Figure 2d) which is discussed in more detail below. Aromatic stacking between adjacent benzimidazole capping groups and phenyl groups are also observed, as expected, down the a axis. Hirshfeld Surface Analysis. The interactions within this structure were further analyzed by Hirshfeld surface analysis. Hirshfeld surface analysis is an extremely useful tool for visualizing interactions within crystal structures,24−26 both graphically through fingerprint plots and in the variety of surfaces that can be mapped onto the molecule of interest. In Hirshfeld surface analysis, the distances of an atom external or internal to the Hirshfeld surface are denoted as de and di, respectively. Thus, an interaction between two atoms can be represented by a (de, di) pair. These values are then binned into intervals of 0.01 Å (essentially a pixel on the Hirshfeld surface) and can be graphically represented as a fingerprint plot.27 The fingerprint plot for benzimidazole-diphenylalanine shows a distinctive set “double spikes”, which represent close O···H and N···H interactions (Figure 3). The symmetrical
O···H interactions comprise a significant proportion of the Hirshfeld surface, at 22.5%. They are undoubtedly responsible for the main structural feature seen in the crystal structure of benzimidazole-diphenylalanine, the infinite chain of hydrogen bonding between amide groups down the a axis. The two main interactions are due to hydrogen bonding between corresponding amides in adjacent molecules. This means that the amide closest to the benzimidazole capping group interacts with the corresponding amide from an adjacent capping group (Figure 4, green circles), which confirms the parallel β-sheet arrange-
Figure 4. Hirshfeld surface displaying dnorm, with the main structure directing interactions highlighted in green (amide hydrogen bonding) and orange (double interaction between carboxylate and capping group).
ment. The interaction distances between adjacent amides 1 (closest to capping group) 2 (closest to C-terminus) are 2.37 and 2.39 Å, respectively. Other O···H interactions are slightly longer and as such are observed as fainter red spots on the dnorm surface. Both of these interactions involve the carbonyl oxygen at the C-terminus of the peptide. One interaction is between this oxygen and a methylene proton from an adjacent capping group (2.43 Å) and the other is with a hydrogen from the C2 carbon of the benzimidazole capping group. Although this interaction is longer (2.67 Å) than for the β-sheet network, it plays a crucial role in the ability of benzimidazole-diphenylalanine to form a two-dimensional arrangement, allowing crystallization to occur. The aforementioned longer O···H contact is actually part of a double interaction, where the other interaction is between a protonated carboxylic acid at the peptide’s C-terminus and the N3 nitrogen (1.83 Å, Figure 4, orange circles). Although N···H interactions comprise only 6.1% of the Hirshfeld surface, it is this double interaction that allows the structure to be extended along the b axis and form ordered two-dimensional sheets, resulting in crystallization. In this way, it can be seen that the choice of capping group is vital to the ability of the structure to be able to form either crystalline or gel networks. Coexistence of Crystal and Gel Network. Interestingly, AFM micrographs of benzimidazole-diphenylalanine show the coexistence of both a fiber phase and a crystalline phase. These striking images show how short, helical fibers 2 nm in height and with a pitch of approximately 50 nm are intertwined around much larger, irregular block shaped nanocrystals (Figure 5a and b). The diameter of the shorter fibers suggests that these are molecular fibers; however, the coexistence of the nanocrystals indicates that there is a competing process between gelation and crystallization. Images taken after complete air-drying of the sample still show the presence of nanocrystallites and fibers (Figure 5c and d). This may explain
Figure 3. Fingerprint plots displaying all contacts (a), only O···Hbased interactions (b), N···H-based interactions (c), and H···H-based interactions (d).
nature of these spikes indicates that the close O···H and N···H based interactions are reciprocal. Another spike can be observed along the de = di diagonal; this is due to short H··· H interactions. The lack of “wings” in the fingerprint plot28 suggests that there is an absence of any CH···π interactions within the structure. The dnorm surface is possibly the most informative property, in terms of interactions, that can be mapped onto a Hirshfeld surface. Here, the distance between an atom internal and external to the Hirshfeld surface, di and de, respectively, is calculated and compared to the sum of the van der Waals radii of the two atoms.29 This is translated into a red-white-blue color scheme where red represents interactions shorter than the sum of the van der Waals radii and blue denotes distances longer than the van der Waals radii. C
DOI: 10.1021/acs.langmuir.5b03963 Langmuir XXXX, XXX, XXX−XXX
Article
Langmuir
whether the crystal structure is an accurate representation of the molecular structure of the native gel. Comparison to Fmoc-FF. The effect of the benzimidazole capping group on gelation and crystallization behavior can be seen when comparing benzimidazole-diphenylalanine to the most well-known dipeptide gelator, Fmoc-diphenylalanine (Fmoc-FF).35−37 Although the variation of mechanical and morpohological properties of Fmoc-FF as a function of gelation method, concentration and additives is well documented,38 discrepancies can still exist between laboratories due to different sample preparation conditions. To this end, we prepared Fmoc-FF hydrogels using a pH switch method identical to that used for benzimidazolediphenylalanine. From the rheology frequency sweep and strain sweep experiments (Figures S7 and S8), we see that while the hydrogel strength of Fmoc-FF is only slightly higher than for our system, distinct differences can be seen in the strain sweep. Here the linear viscoelastic region persists only up until 1% strain, compared to 10% strain for benzimidazolediphenylalanine. This is most likely due to the absence of crystalline domains within the hydrogel. The lack of crystalline domains within this hydrogel were confirmed through AFM images obtained for Fmoc-FF (Figure S9), which show individual nanofibers of 2 nm in diameter and bundles of up to 12 nm in diameter. This correlates well with previous observations. Although Fmoc-FF has been observed to crystallize,13 this phenomenon was limited to acetone−water gels, whereas for benzimidazole-diphenylalanine, crystals were observed from both the pH switched hydrogel (i.e., no organic solvents present) and from an acetonitrile−water mixture. In Fmoc-FF, there is no competing crystallization versus gelation process visible for pH switched gels. This is compared to benzimidazole-diphenylalanine, where not only have these competing processes been visualized, but the crystal structure obtained is most likely very similar to that observed within the gel phase.
Figure 5. Gels of benzimidazole-diphenylalanine prepared at 0.1% (w/ v), imaged after drying in air overnight (a,b) and over 3 days (c, d).
the high strain tolerance of these hydrogels (Figure 1d), as most capped dipeptides that we have previously synthesized fail at strains of less than 10%. One explanation for this may be that this hybrid network redistributes any applied strain into shifting the nanocrystalline domains within the gel. Supramolecular hydrogels have been used previously as matrices for crystallization of various pharmaceuticals and biominerals,30,31 and crystal structures of various hydro and organogelators have been elucidated,32−34 but typically the crystal and gel phases do not coexist. Powder X-ray diffraction (PXRD) was performed on both the xerogel and native gels of benzimidazole-diphenylalanine. The xerogel clearly shows the presence of crystalline peaks which correlate quite well to the simulated powder X-ray diffraction pattern from the single crystal structure (Figure 6a),
■
CONCLUSIONS
In conclusion, we have synthesized a short N-capped peptide, benzimidazole-diphenylalanine, which possesses the uncommon ability to form both stable hydrogels and also single crystals. We show that hydrogels formed from this dipeptide display an intermediate stiffness, however are quite resilient toward oscillatory strain, possibly due to the coexistence of crystals and fibers within the gel structure. From the crystal structure we see parallel β-sheet formation down the a axis and an intriguing bidentate interaction between the protonated carboxylic acid and the benzimidazole capping group, which allows the structure to be extended along the b axis and crystallization to occur. This parallel β-sheet arrangement is contrary to currently accepted models of gelation in short peptides; however, these results in combination with recent modeling studies22 suggest this may need to be revisited. AFM images remarkably show the coexistence of a nanocrystalline and fiber phase, whereby short, helical nanofibers 2 nm in diameter are intertwined through nanocrystals of the peptide. This coexistence has implications for fiber growth mechanisms and the future rational design of peptide gelators, where the balance between gelation and crystallization inevitably controls the properties of the resultant materials.
Figure 6. Overlay of PXRD pattern simulated from the crystal structure with PXRD pattern obtained from a xerogel of benzimidazole-diphenylalanine (a) and PXRD pattern of the native gel (b). In both images, peaks at low 2θ are likely not visible due to amorphous aggregates and the large peak at 2θ ≈ 43° is from the sample holder.
suggesting a similar molecular arrangement. The PXRD of the native gel, however, is quite different, with broad peaks indicating that the hydrogel has an amorphous nature (Figure 6b). A peak can be observed at 2θ ≈ 20°, which is also seen in the X-ray diffraction pattern of the xerogel, however any other crystalline peaks resulting from the presence of nanocrystals within the structure would likely be obscured by the large amount of amorphous scattering at low 2θ, thus it is unclear D
DOI: 10.1021/acs.langmuir.5b03963 Langmuir XXXX, XXX, XXX−XXX
Article
Langmuir
■
supramolecular nanofibers and hydrogels. Angew. Chem., Int. Ed. 2014, 53, 1921−1927. (10) Martin, A. D.; Robinson, A. R.; Thordarson, P. Biocompatible small peptide super-hydrogelators bearing carbazole functionalities. J. Mater. Chem. B 2015, 3, 2277−2230. (11) Draper, E. R.; Eden, E. G. B.; McDonald, T. O.; Adams, D. J. Spatially resolved multicomponent gels. Nat. Chem. 2015, 7, 848−852. (12) Martin, A. D.; Robinson, A. B.; Mason, A. F.; Wojciechowski, J. P.; Thordarson, P. Exceptionally strong hydrogels through selfassembly of an indole-capped dipeptide. Chem. Commun. 2014, 50, 15541−15544. (13) Tang, C.; Smith, A. M.; Collins, R. F.; Ulijn, R. V.; Saiani, A. Fmoc-diphenylalanine self-assembly mechanism induces apparent pKa shifts. Langmuir 2009, 25, 9447−9453. (14) Raeburn, J.; Mendoza-Cuenca, C.; Cattoz, B. N.; Little, M. A.; Terry, A. E.; Cardoso, A. Z.; Griffiths, P. C.; Adams, D. J. The effect of solvent choice on the gelation and final gel properties of Fmocdiphenylalanine. Soft Matter 2015, 11, 927−935. (15) Houton, K. A.; Morris, K. L.; Chen, L.; Schmidtmann, M.; Jones, J. T. A.; Serpell, L. C.; Lloyd, G. O.; Adams, D. J. On crystal versus fiber formation in dipeptide hydrogelators systems. Langmuir 2012, 28, 9797−9806. (16) Merrifield, R. B. Solid phase peptide synthesis. 1. Synthesis of a tetrapeptide. J. Am. Chem. Soc. 1963, 85, 2149. (17) Adams, D. J.; Butler, M. F.; Frith, W. J.; Kirkland, M.; Mullen, L.; Sanderson, P. A new method for maintaining homogeneity during liquid-hydrogel transitions using low molecular weight hydrogelators. Soft Matter 2009, 5, 1856−1862. (18) Fleming, S.; Frederix, P. W. J. M.; Ramos Sasselli, I.; Hunt, N. T.; Ulijn, R. V.; Tuttle, T. Assessing the utility of infrared spectroscopy as a structural diagnostic tool for β-sheets in self-assembling aromatic amphiphiles. Langmuir 2013, 29, 9510−9515. (19) Awhida, S.; Draper, E. R.; McDonald, T. O.; Adams, D. J. Probing gelation ability for a library of dipeptide gelators. J. Colloid Interface Sci. 2015, 455, 24−31. (20) Yan, C.; Pochan, D. J. Rheological properties of peptide-based hydrogels for biomedical and other applications. Chem. Soc. Rev. 2010, 39, 3528−3540. (21) Marchesan, S.; Styan, K. E.; Easton, C. D.; Waddington, L.; Vargiu, A. V. Higher and lower supramolecular orders for the design of self-assembled heterochiral tripeptide hydrogel biomaterials. J. Mater. Chem. B 2015, 3, 8123. (22) Mu, X.; Eckes, K. M.; Nguyen, M. M.; Suggs, L. J.; Ren, P. Experimental and computational studies reveal an alternative supramolecular structure for Fmoc-dipeptide self-assembly. Biomacromolecules 2012, 13, 3562−3571. (23) Spackman, M. A.; Jayatilaka, D. Hirshfeld surface analysis. CrystEngComm 2009, 11, 19−32. (24) Liyanage, W.; Brennessel, W. W.; Nilsson, B. L. Spontaneous transition of self-assembled hydrogel fibrils into crystalline microtubes enables a rational strategy to stabilize the solid state. Langmuir 2015, 31, 9933−9942. (25) Sato, S.; Yamasaki, T.; Isobe, H. Solid-state structures of peapod bearings composed of finite single-wall carbon nanotubes and fullerene molecules. Proc. Natl. Acad. Sci. U. S. A. 2014, 111, 8374−8379. (26) Jena, H. S. Effect of non-covalent interaction on the diastereoselective self-assembly of Cu(II) complexes containing a racemic Schiff base in a chiral self-discriminating process. New J. Chem. 2014, 38, 2486−2499. (27) McKinnon, J. J.; Spackman, M. A.; Mitchell, A. S. Novel tools for visualizing and exploring intermolecular interactions in molecular crystals. Acta Crystallogr., Sect. B: Struct. Sci. 2004, B60, 627−668. (28) Martin, A. D.; Britton, J.; Easun, T. E.; Blake, A. J.; Lewis, W.; Schroder, M. Hirshfeld surface investigation of structure-directing interactions within dipicolinic acid derivatives. Cryst. Growth Des. 2015, 15, 1697−1706. (29) McKinnon, J. J.; Jayatilaka, D.; Spackman, M. A. Towards quantitative analysis of intermolecular interactions with Hirshfeld surfaces. Chem. Commun. 2007, 3814−3816.
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.langmuir.5b03963. Additional data including the synthesis and characterization of the peptide and details of AFM, CD and other measurements (PDF) Crystallographic data for the peptide (CIF) CheckCIF/PLATON report for the peptide (PDF)
■
AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. Fax: +61 (0)2 9385 6141. Tel: +61 (0)2 9385 4478. *E-mail:
[email protected] Author Contributions
All authors have given approval to the final version of the manuscript. Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS We would like to thank the Mark Wainwright Analytical Centre (UNSW) for access to instruments. We acknowledge the Australian Research Council for Discovery Project Grant (DP130101512), an ARC Centre of Excellence Grant (CE140100036), and a Future Fellowship to P.T. (FT120100101) and the Australian government for Ph.D. scholarship to J.P.W.
■
REFERENCES
(1) Banwell, E. F.; Abelardo, E. S.; Adams, D. J.; Birchall, M. A.; Corrigan, A.; Donald, A. M.; Kirkland, M.; Serpell, L. C.; Butler, M. F.; Woolfson, D. N. Rational design and application of responsive alphahelical peptide hydrogels. Nat. Mater. 2009, 8, 596−600. (2) Yao, X. P.; Liu, Y.; Gao, J.; Yang, L.; Mao, D.; Stefanitsch, C.; Li, Y.; Zhang, J.; Ou, L. L.; Kong, D. L.; Zhao, Q.; Li, Z. J. Nitric oxide releasing hydrogel enhances the therapeutic efficacy of mesenchymal stem cells for myocardial infarction. Biomaterials 2015, 60, 130−140. (3) Ikeda, M.; Tanida, T.; Yoshii, T.; Kurotani, K.; Onogi, S.; Urayama, K.; Hamachi, I. Installing logic-gate responses to a variety of biological substances in supramolecular hydrogel-enzyme hybrids. Nat. Chem. 2014, 6, 511−518. (4) Adler-Abramovich, L.; Gazit, E. The physical properties of peptide supramolecular assemblies: from building block association to technical applications. Chem. Soc. Rev. 2014, 43, 6881−6893. (5) Berns, E. J.; Sur, S.; Pan, L.; Goldberger, J. E.; Suresh, S.; Zhang, S.; Kessler, J. A.; Stupp, S. I. Aligned neurite outgrowth and directed cell migration in self-assembled monodomain gels. Biomaterials 2014, 35, 185−195. (6) Newcomb, C. J.; Sur, S.; Ortony, J. H.; Lee, O.-S.; Matson, J. B.; Boekhoven, J.; Yu, J. M.; Schatz, G. C.; Stupp, S. I. Cell death versus cell survival instructed by supramolecular cohesion of nanostructures. Nat. Commun. 2014, 5, 3321. (7) Lozano, R.; Stevens, L.; Thompson, B. C.; Gilmore, K. J.; Gorkin, R.; Stewart, E. M.; Panhuis, M. I. H.; Romero-Ortega, M.; Wallace, G. G. 3D printing of layered brain-like structures using peptide-modified gellan gum substrates. Biomaterials 2015, 67, 264−273. (8) De Santis, E.; Ryadnov, M. G. Peptide self-assembly for nanomaterials: the old new kid on the block. Chem. Soc. Rev. 2015, 44, 8288. (9) Hsu, S.; Lin, Y.; Chang, J.; Liu, Y.; Lin, H. Intramolecular interactions of a phenyl/perfluorophenyl pair in the formation of E
DOI: 10.1021/acs.langmuir.5b03963 Langmuir XXXX, XXX, XXX−XXX
Article
Langmuir (30) Ming, J. F.; Zuo, B. Q. Crystal growth of calcium carbonate in silk fibroin/sodium alginate hydrogel. J. Cryst. Growth 2014, 386, 154− 161. (31) Saridakis, E.; Chayen, N. E. Imprinted polymers assisting protein crystallization. Trends Biotechnol. 2013, 31, 515−520. (32) Steed, J. W. Anion-tuned supramolecular gels: a natural evolution from urea supramolecular chemistry. Chem. Soc. Rev. 2010, 39, 3686−3699. (33) Goh, C. Y.; Becker, T. E.; Brown, D. H.; Skelton, B. W.; Jones, F.; Mocerino, M.; Ogden, M. I. Self-inclusion of proline-functionalised calix[4]arene leads to hydrogelation. Chem. Commun. 2011, 47, 6057− 6059. (34) Webb, J. E. A.; Crossley, M. J.; Turner, P.; Thordarson, P. Pyromellitamide aggregates and their response to anion stimuli. J. Am. Chem. Soc. 2007, 129, 7155−7162. (35) Reches, M.; Gazit, E. Self-assembly of peptide nanotubes and amyloid-like structures by charged-termini-capped diphenylalanine peptide analogues. Isr. J. Chem. 2005, 45, 363−371. (36) Jayawarna, V.; Ali, M.; Jowitt, T. A.; Miller, A. F.; Saiani, A.; Gough, J. E.; Ulijn, R. V. Nanostructured Hydrogels for ThreeDimensional Cell Culture Through Self-Assembly of Fluorenylmethoxycarbonyl−Dipeptides. Adv. Mater. 2006, 18, 611−614. (37) Mahler, A.; Reches, M.; Rechter, M.; Cohen, S.; Gazit, E. Rigid, Self-Assembled Hydrogel Composed of a Modified Aromatic Dipeptide. Adv. Mater. 2006, 18, 1365−1370. (38) Raeburn, J.; Pont, G.; Chen, L.; Cesbron, Y.; Levy, R.; Adams, D. J. Fmoc-diphenylalanine hydrogels: understanding the variability in reported mechanical properties. Soft Matter 2012, 8, 1168−1174.
F
DOI: 10.1021/acs.langmuir.5b03963 Langmuir XXXX, XXX, XXX−XXX
