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Published in final edited form as: Protein Pept Lett. 2020 Jan 1;27(8):688–697. doi: 10.2174/0929866527666200212123542

Self-Assembly of Cyclic Dipeptides: Platforms for Functional Materials

Yu Chen 1, Kai Tao 1, Wei Ji 1, Pandeeswar Makam 1, Sigal Rencus-Lazar 1, Ehud Gazit 1,2,*
PMCID: PMC7616926  EMSID: EMS117013  PMID: 32048950

Abstract

Supramolecular self-assembled functional materials comprised of cyclic dipeptide building blocks have excellent prospects for biotechnology applications due to their exceptional structural rigidity, morphological flexibility, ease of preparation and modification. Although the pharmacological uses of many natural cyclic dipeptides have been studied in detail, relatively little is reported on the engineering of these supramolecular architectures for the fabrication of functional materials. In this review, we discuss the progress in the design, synthesis, and characterization of cyclic dipeptide supramolecular nanomaterials over the past few decades, highlighting applications in biotechnology and optoelectronics engineering.

Keywords: Self-assembly, biomaterial, cyclic dipeptide, bionanotechnology, optoelectronic, photoluminescence

1. Introduction

Biological molecular self-assemblies, such as DNA double helix, enzymes quaternary structure, and ribosomes, are common in nature, playing critical physiological functions in vivo. Compared to proteins, peptides have received significant attention as potential nanotechnology building blocks due to their simple structure, flexibility, and variability in molecular design [1–6]. In the past few decades, many short peptides and their synthetic analogues have been assembled into structures that are widely used in nanotechnology [7–16]. One of the prominent examples is diphenylalanine (FF), a self-assembling dipeptide sequence initially identified as the minimal core recognition motif of amyloid β-protein (Aβ), the amyloidogenic polypeptide associated with Alzheimer’s disease [14]. FF has been shown to self-assemble into a diversity of nanostructures of various applications, including biosensing [17, 18], biomedical, and other bio-nanotechnology-based electronic [19, 20], photonic [21–23] and energy generation and storage [24, 25].

Although proteinogenic peptides and their derivatives are promising candidates for molecular self-assembly applications, they are enzymatically degradable under physiological conditions and lack molecular rigidity which is a prerequisite for diverse applications. Peptide derivatives, containing either configured or non-coded amino acids, and cyclic peptides have been used to overcome the problem of enzymatic degradation of natural peptides [26]. In particular, cyclic dipeptides (CDPs) exhibit superior biological activity, protease resistance and conformational rigidity compared to their linear analogs, resulting in their improved ability to specifically interact with biological targets [27–29]. In nature, CDP represents a large class of secondary metabolites containing 2,5-diketopiperazine (DKP) heterocycles, which are ubiquitous and evolutionarily conserved in a variety of organisms, from bacteria to humans [30–37]. Thus, the particular structure selected during evolution has unique advantages in terms of biological activity and stability, making it an attractive scaffold molecule for pharmaceutical applications [32, 38].

CDPs and their derivatives obtained from natural sources are an essential class of active molecules with biological functions [39–41]. For example, cyclo-(His-Pro) has been demonstrated to be derived from thyrotropin-releasing hormone (TRH) metabolism and is indeed de novo synthesized in vivo [42, 43]. Although numerous CDP natural products have been isolated and characterized for use in pharmacology, relatively little is known about engineering their architectures for functional and smart materials [44]. In this review, the aim is to provide a comprehensive summary of design strategies used to engineer the molecular selfassembly of CDPs into functional nano- and microarchitectures and supramolecular gels with potential applications in the biotechnology and optoelectronic engineering fields.

2. Synthesis of CDPS

As a head-to-tail cyclization of the linear dipeptide, a CDP is typically formed by an unprotected linear peptide under basic conditions, given that head-to-tail refolding is not obstructed by steric constraints. Given the significant potential of CDPs for various technologies, their preparation methods are actively developed, including solid-phase synthesis, microwave-assisted cyclization of dipeptides in water, and solid-state synthesis [28, 45–47]. The commonly used method employs the Nα-Boc strategy, that is, coupling of an N-Boc-protected α-amino acid with an α-amino acid ester, followed by N-Boc deprotection and intramolecular cyclization. Based on this strategy, various efficient and ecofriendly methods for synthesizing CDPs from N-Boc protected dipeptide ester have been reported, such as the use of water to deprotect N-Boc [48, 49] or cyclizing N-Boc protected amino esters under solvent-free condition [50]. Furthermore, the use of microwave heating has proven to be advantageous in solid phase peptide synthesis, allowing to shorten the reaction time for peptide coupling and Nα-Boc / Fmoc deprotection and increase the purity of the crude peptide [45, 51].

Although this synthesis methodology is highly practical for the production of cyclic dipeptides, it requires a challenging multi-step purification. In contrast, the solid-state synthesis method allows cyclic dipeptides to be obtained in one step without any by-products. The solid-state synthesis of cyclic dipeptides has been developed in detail by using amino acids or a linear dipeptide as the source. Recently, Ziganshin et al. investigated the thermal properties of Phe-Phe, Leu-Leu, Ile-Ala, and Gly-Gly dipeptides and their cyclization behavior upon heating [52–54]. A correlation between the side residue structure of the dipeptides and the onset temperature of the cyclization reaction in solid-state was demonstrated. Our group reported an efficient yet straightforward preparation protocol of cyclo-diphenylalanine (cyclo-FF) nanotubes through thermal vapor deposition of the corresponding linear dipeptide under vacuum based on the solid-state synthesis method [55]. The linear FF dipeptide evaporated and intramolecularly cyclized at 220 °C under vacuum conditions to form micrometer aligned cyclo-FF nanotubes in situ on a substrate, as shown in Figure 1. Subsequently, Park and co-workers synthesized single-crystalline cyclo-FF nanowires by the vapor-transport method [56]. Powder X-ray diffraction and thermogravimetric analysis showed that the FF powder lost water and converted into cyclo-FF during the vapor-transport process, thus supporting the concept of intramolecular cyclization during physical vapor deposition.

Figure 1.

Figure 1

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Schematic of the synthesis of cyclo-FF through the thermal vapor deposition technique. During evaporation, the linear diphenylalanine peptide heated to 220 °C gave rise to a cyclic structure which was then assembled on a substrate to form ordered vertically aligned nanotubes. Figures reproduced with permission from ref. 55. (A higher resolution / colour version of this figure is available in the electronic copy of the article).

3. Applications of Self-Assembled CDPS

3.1. Mechanical Properties

In addition to the biological activity, CDPs are ideal candidates for engineering mechanical performance due to their extensive hydrogen bonding formation sites [57]. Furthermore, the possibility of introducing various substituents into the DKP-ring and the side residue constituting the amino acids allows producing molecular solid-state structures with exceptional mechanical properties. The pioneering work of Tuomas and Markus has demonstrated that amyloid fibrils with a dense backbone of hydrogen bonding network yield high Young’s modulus values ranging between 0.2-14 GPa [58]. Unlike linear peptides, CDP scaffolds show higher molecular rigidity, which originates from the four hydrogen-bonding sites on the DKP-ring (two donors and two acceptors), as shown in Figure 2a. Therefore, by controlling the self-assembly process of CDPs, biomaterials with desired mechanical properties can be readily synthesized. Kai and colleagues have demonstrated that molecular packings of cyclo-phenylalanine-tryptophan (cyclo-FW) can impart unique rigidity, with Young’s modulus values of 17.4 ~24.0 GPa [59, 60] (Figure 3a-c). Furthermore, the self-assembly mechanism of CDPs can be switched between a 1D molecular chain and a 2D layer by modulating the type of amino acid or the stereochemistry of the α-carbon atom, as depicted in Figure 2b-c [57]. Govindaraju et al. have demonstrated that mechanical performance can be tailored through stereochemistry of certain CDPs (cyclized alanine (LL-Ala and LD-Ala) and phenylglycine (LL-Phg and LD-Phg)) [61] (Figure 3d-g, Figure 4). The mechanical performance of CDPs is considered to be determined by the peptide composition and stereochemistry as well as the indentation plane during the measurement.

Figure 2.

Figure 2

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Molecular self-assembly of CDPs. (a) The four hydrogen-bonding sites of CDPs. (b) CDP molecular chains. (c) CDP molecular layer. (A higher resolution / colour version of this figure is available in the electronic copy of the article).

Figure 3.

Figure 3

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(a) Molecular structures and the corresponding crystal morphologies of cyclo-FW. (b) Crystallographic structure of cyclo-FW, the hydrogen bond between the main chain DKP rings, the water bridge and the hydrophobic region consisting of the aromatic moiety of the side chain are magnified in the right panels and labeled “1”, “2” and “3”, respectively. (c) Young’s modulus of cyclo-FW. (d-g) (i) Molecular structures, (ii) optical microscopy images and (iii) crystalline molecular packing of (d) LL-Ala, (e) LD-Ala, (f) LL-Phg, and (g) LD-Phg. Scale bar is 1 mm. Figures reproduced with permission from (a-c) ref. 59, (d-g) ref. 61. (A higher resolution / colour version of this figure is available in the electronic copy of the article).

Figure 4.

Figure 4

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Plot of elastic modulus (E) verses strength for various materials and cyclic dipeptides. Figures reproduced with permission from ref. 61. (A higher resolution / colour version of this figure is available in the electronic copy of the article).

3.2. Piezoelectric & Triboelectric Properties

The low biocompatibility or engineerability of conventional inorganic materials limits their widespread application for power harvesting in biological systems. However, self-assembled CDP structures are ideal components for eco-friendly photovoltaic energy harvesting devices due to their inherent biocompatibility, robust mechanical properties and flexible functionalization. Our group recently demonstrated that tryptophan-based simple CDPs, such as cyclo-glycine-tryptophan (cyclo-GW) (Figure 5a, b) and cyclo-FW, form mechanically robust crystals through a supramolecular packing combining dense parallel β-sheet hydrogen bonding and herringbone edge-to-face aromatic interactions [59, 60]. The nocentrosymmetric structures of cyclo-GW and cyclo-FW mediated by oriented hydrogen bonds and aromatic packing networks lead to internal polarization, resulting in piezoelectric properties (Figure 5c). Indeed, these tryptophan-based CDP crystals were used to fabricate a generator with an open-circuit voltage of 1.2 V and a short-circuit current (Isc) of 1.75 nA (Figure 5d-g). Furthermore, since CDPs can be synthesized by heating of the corresponding linear peptide, it is feasible to develop a simple yet large-scale CDP nano-array through a thermal evaporation process. Heo et al. reported high performance cyclo-FF-based triboelectric energy generators (Figure 5h-i) [62]. A thermal evaporation method was utilized to a deposit cyclo-FF nanowire array on a variety of substrates over a large area. The results indicated that owing to the phenylalanine residues in the peptide building block and structural complexity, and the peptide nanowire array was stable under ambient conditions, moisture and even in water or TBS buffer, which is termed the “lotus-effect”. Eventually, the proof-of-concept triboelectric device was successfully implemented owing to such stable features. The power outputs of the devices were significantly enhanced using a simple corona discharge treatment, which reached a maximum power density of ~73.7 mW/m [2], enough to illuminate more than one hundred light emitting diodes (Figure 5j-m).

Figure 5.

Figure 5

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(a) cyclo-GW molecular structure. (b) Scanning Electron Microscopy (SEM) image of the cyclo-GW crystals. (c) 3D surface plot of computed piezoelectric coefficients of cyclo-GW single crystal calculated by DFT. (d) Schematic configuration of the generator as a direct power source using cyclo-GW crystals as active components. (e) Open-circuit voltage and (f) short-circuit current obtained from the generator and the linear dependence (g) of the open-circuit voltage on the applied force. (h) The fabrication procedure of a cyclo-FF nanowire array. (i) The triboelectric energy generator fabricated based on cyclo-FF nanowire array. (j) Voltage and current enhancements depending on bias of corona discharge process. (k) Open-circuit voltage and (l) short-circuit current obtained from the generator after a corona discharge treatment. (m) Cyclo-FF triboelectric energy generator demonstrated to support the requirement of 126 LEDs (The power consumption of each LED was ~40 mW). Figures reproduced with permission from (a-g) ref. 60, (h-m) ref. 62. (A higher resolution / colour version of this figure is available in the electronic copy of the article).

3.3. Optical Properties

Self-assembled CDP nanostructures have inherent optical absorption and photoluminescence in the UV and visible regions due to the quantum-confined structures formated mediated by the hydrogen bonding and aromatic interactions in the assemblies [63]. For example, when excited at 367 nm, cyclo-FF single crystals showed strong blue fluorescence emission centered at 465 nm [21]. Gazit et al. demonstrated certain CDPs, such as cyclo-FW and cyclo-WW (Figure 6a), to be prone to dimerization into quantum-confined nanostructures displaying intrinsic photoluminescence from the visible to the near-infrared region (420 nm to 820 nm), which could be tuned by modifying the self-assembly process [64], as shown in Figure 6b-c. The biocompatibility and wide-spectrum emission features make these supramolecular structures potentially applicable for in vivo bio-imaging and as the phosphors for LEDs (Figure 6d-g).

Figure 6.

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(a) Cyclo-FW and cyclo-WW molecular structures. (b) Atomic force microscopy image of dimeric assemblies of cyclo-WW + Zn(II). (c) Schematic diagram showing the self-assembly mechanism of peptide supramolecular structures. (d) Schematic presentation of the LED setup using cyclo-WW + Zn(II) assembled as phosphors. (e) Spectroscopic characterization of the LED photoluminescence using three excitation wavelengths. (f) Cytotoxicity test of the cyclo-WW + Zn(II) nanospheres towards B16-BL6, HaCaT, and MCF7 cells. (g) In vivo whole body near-infrared fluorescence imaging following subcutaneous injection of the cyclo-WW + Zn(II) nanospheres (50 μL, 2.7 mM) into nude mice. (h) Formation of ultralong crystalline cyclo-FF platelets via hydrothermal method. (i, j) SEM images of crystalline cyclo-FF platelets. (k-m) Optical waveguiding of curved peptide platelets with the incorporation of Nile Red as a guest dye. Figures reproduced with permission from (a-g) ref. 64, (h-m) ref. 65. (A higher resolution / colour version of this figure is available in the electronic copy of the article).

Due to the ordered architectures and facile optical tuneability, CDPs are promising building blocks for next generation, eco-friendly optoelectronic devices, such as optical waveguides. Yan et al. demonstrated that the use of solvothermal treatment to accelerate the intramolecular cyclization of linear FF resulted in ultralong crystalline peptide nanobelts [65] (Figure 6h). When formaldehyde was introduced into the cyclo-FF system, slab or bent optical waveguide transmission capabilities were observed for conventional straight and curved peptide crystals (Figure 6i-j). In the bent optical waveguide, the emitted red light could propagate along the curved axial and be coupled out at the other end (Figure 6k-m).

3.4. Stimulus-responsive Properties

CDP is designed for the superior hydrogen bonding capabilities of their skeleton (DKP) and other noncovalent interactions and can be used as artificial multifunctional scaffolds [66]. In recent years, a wide range of stimuli-responsive properties has been achieved, such as thixotropic [67–69], photoresponsive [70], and thermoresponsive [71] properties. Hoshizawa et al. designed CDP-based hydrogelators comprised of cyclo(L-Phe-L-Asp) derivatives and studied the gel tendency and behavior during gel-sol-gel transitions [68] (Figure 7a, CDP 1-3). It has been reported that the hydrogels obtained from these CDPs not only formed a thermally/isothermally reversible physical gel in several solvents, but also exhibited shear-force-induced reversible thixotropic behavior. As demonstrated by polarized optical microscopy analysis, the thixotropic behavior corresponded to three different structures on a macroscopic scale, and in this case, the gel-sol-gel transition resulted from the destruction of the van der Waals forces among the under-sheared alkylene chains (Figure 7b-d).

Figure 7.

Figure 7

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(a) Preparation of hydrogelators based on CDPs. (b-d) Polarized-light optical microscopy images of (b) the gel, (c) sol, and (d) reformed gel of compound CDP 1. (e) The supramolecular hydrogel (left panel) formed from CDP 4, which becomes sol (right panel) upon UV light irradiation. (f) Molecular structure of CDP 5. (g) Proposed self-assembly process of CDP 5 nanotubes. CDP-DAs are first selfassembled into (I) bi-layered plates, and then (II, III) gradually roll up to form (IV) single-wall or (V, VI) multiwall nanotubes. (h) Reversible thermochromic property of CDP 5 upon heating and cooling, (i) Plots of absorbance intensity at 650 nm as a function of thermal cycles. Figures reproduced with permission from (a-d) ref. 68, (e) ref. 70, (f-i) ref. 72. (A higher resolution / colour version of this figure is available in the electronic copy of the article).

Pianowski et al. developed a CDP-based (CDP 4) low molecular weight gelator (LMWG) with multi-stimulation responsiveness and self-healing capabilities (Figure 7e) [70]. By introducing a photosensitive moiety (trans-azobenzenes) and a cationic amino acid residue, the LMWGs self-assembled into a photoresponsive gel that tightly bound long dsDNA oligomers within their fibrous structures and efficiently released them upon light irradiation. The gel-sol conversion of the LMWG responded to UV-(365 nm) and visible-light (460 nm), respectively, due to the light-induced conversion from planar trans-azobenzenes to non-planar cis-azobenzenes. In addition, the anti-cancer drug doxorubicin could be encapsulated in these gels and released by photon stimulation.

Kim and co-workers prepared stable and reversibly thermochromic CDP (CDP 5) nanotubes, as shown in Figure 7f, by introducing diacetylenic amphiphiles (CDP-DAs) [72]. The CDP-DA tubular assemblies produced a blue color under UV illumination, which could be switched between blue and red by heating and cooling at 90 and 25 °C, respectively (Figure 7g-i). The reversible thermochromic transition originated from intermolecular hydrogen bonding, as evidenced by NMR and Fourier-transform infrared spectroscopy. As suggested by the authors, the strategy of a CDP platform modified with a stimuli-responsive moiety potentially provides a better interface between biotechnology and biomedicine.

3.5. Hydrogel-forming CDPs

Molecular gels formed by self-assembly of CDPs combine the unique properties of LMWG, their dynamic properties and the versatility of amino acid-based CDPs, thus providing an opportunity to develop soft materials for further applications. Govindaraju et al. rationally designed a series of tert-butyloxycarbonyl (OtBu) protected CDPs, cyclo(L-Tyr-L-Glu(OtBu), cyclo(L-Phe-L-Glu(OtBu), cyclo(L-Phe-L-Asp(OtBu), and cyclo(L-Leu-L-Glu-(OtBu))) derived hydrogelators, and studied the minimum structural requirements for gelation in both organic and aqueous media and the ability to form a gel in a biocompatible solvent in situ [73]. Density Functional Theory (DFT) demonstrated that the stability of the microstructure depends mainly on the synergetic effect of the intermolecular N-H…O hydrogen bonding, the hydrophobic interactions among the tBoc groups and π-π stacking interactions between phenyl rings. Through a detailed characterization of CDP hydrogels, the authors showed that curcumin, an anti-cancer drug, could be loaded into the gel during in situ gelation, implying a promising potential for controlled drug release applications.

Yan et al. developed a hydrogel based on cyclo-Leu-Phe, showing excellent rheological properties and biosafety [74]. The results showed that the hydrogen bonds between the cyclic dipeptide backbones were the dominant driving force for the molecular organization into long-range ordered nanofibers. More interestingly, the CDP was stable under harsh conditions, including the presence of salts, proteins or enzymes, and even in acidic or basic aqueous solutions, demonstrating its potential application as a functional hydrogel in extreme environments.

3.6. Proton Conduction

Metal-Organic Frameworks (MOFs) composed of metal ions and organic ligands have become an important class of proton conductors. Exploring bioligands based on amino acids containing proton carriers (NH4+, imidazole, carboxylic acids, and amines) can provide supramolecular templates in the cross-channels of MOFs, which is critical for achieving high proton conductivity. Lin and colleagues developed two water-stable oxalate-based proton-conducting coordination polymers in the presence of cyclic-dihistidine (cyclo-HH) [75] (Figure 8a). The CDP was introduced into the framework structures through in situ condensations of racemic histidine molecules allowing to synthesize a new class of MOFs formulated (C12H16N6O2)[Zn2(C2O4)3] (SCU-63) (Figure 8b) and (C12H16N6O2)[Mn(C2O4)] (SCU-66) (Figure 8c), which exhibited high proton conductivity in the order of 10-3 S cm-1 at 85 °C under 98% relative humidity (Figure 8d-e). As revealed by single crystal X-ray diffraction analysis, cyclo-HH played different roles in the formation of the two MOFs. In the structure of SCU-63the CDP acted as a structure directing agent located in the interlayer region of the honeycomb-like zinc oxalate layer. In contrast, in the structure of SCU-66, cyclo-HH was used as a bridging ligand to link two manganese atoms through an Mn-N bond. The cyclo-HH frameworks are considered potentially useful proton carriers, as well as provide an efficient pathway for proton transfer.

Figure 8.

Figure 8

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(a) The synthesis process of oxalate-based proton-conducting coordination polymers in the presence of cyclo-HH. (b-c) Crystal structures of (b) SCU-63 and (c) SCU-66. (d) Arrhenius plot of the proton conductivity of (d) SCU-63 and (e) SCU-66 under 98% relative humidity. Figures reproduced with permission from ref. 75. (A higher resolution / colour version of this figure is available in the electronic copy of the article).

Conclusions

Although CDPs are ubiquitous, few of these molecules have been fully discovered. As a result of their morphological and functional flexibility, as well as ease of preparation, modification and regulation, CDPs are recently emerging as promising alternatives to widely used organic counterparts. Combining a rigid molecular skeleton and enhanced enzyme stability under physiological conditions, CDPs show great potential as building blocks the self-assembly biocompatible supramolecular scaffolds to be utilized in human tissues. Furthermore, conjugation of the supramolecular backbone to functional moieties through the side residue can endow CDP scaffolds with special molecular recognition and stimuli response properties. In addition, CDPs also can be used as ligands for MOFs. Compared to other commonly used biomolecules, such as amino acids, nucleobases, saccharides, and linear peptides, CDP-related ligands offer the potential to utilize multiple coordination sites and contain a variety of functional groups which can be advantageous in various fields, such as CO2 capture, separation and catalysis. In addition, CDPs can be incorporated into the frameworks by in situ condensations of amino acid molecules, allowing their simple and eco-friendly synthesis. Moreover, the in situ slow formation of the ligand can ensure sufficient growth of the single crystal to determine through the X-ray single-crystal structure. Finally, the development of CDP-derived LMWGs might lead to potential applications in drug delivery and label-free, real-time monitoring and sensing. This line of research may offer an opportunity to visually track drug release in a spatiotemporal mode and to investigate the metabolic kinetics of cancer drugs in a certain organ or tissue.

Acknowledgements

The authors thank the members of the Gazit laboratory for helpful discussions.

Funding

This work was supported in part by the European Research Council under the European Union Horizon 2020 research and innovation program (No. 694426) (E.G.), and Huawei Technologies Co., Ltd. (E.G.). Y.C. gratefully acknowledges the Center for Nanoscience and Nanotechnology of Tel Aviv University for financial support.

Footnotes

Consent for Publication

Not applicable.

Conflict of Interest

The authors declare no conflict of interest, financial or otherwise.

DISCLAIMER: The above article has been published in Epub (ahead of print) on the basis of the materials provided by the author. The Editorial Department reserves the right to make minor modifications for further improvement of the manuscript.

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