Nucleobase Self-Assembly Codes, Constitutional Transcription of - CHEMICAL BIOLOGY

CHEMICAL BIOLOGY

Nucleobase Self-Assembly Codes, Constitutional Transcription of

Mihail Barboiu, Adaptative Supramolecular Nanosystems Group, Institut Europeen des Membranes, IEM/UMII, Place Eugene Bataillon, Montpellier, France

doi: 10.1002/9780470048672.wecb527

The functional self-organization can be transcribed readily into hybrid nanostructures by using the sol-gel process. Accordingly, we have reported synthetic routes for preparing self-organized systems that have been ''frozen'' in a siloxane matrix, as a straightforward approach to design a novel class of solid hybrid nanomaterials. Nucleobases oligomerization can be an advantageous choice to reinforce the controlled communication between interconnected ''dynamic supramolecular'' and ''fixing siloxane'' systems. Moreover, the different interconverting outputs that nucleobases may form by oligomerization define a dynamic polyfunctional diversity that may be ''extracted selectively'' by sol-gel polymerization in solid state under the intrinsic stability of the different nucleobase-pairing and G-quadruplex-based systems. The nucleobase-type hybrid materials presented in this review unlock the door to the new self-organized materials world paralleling that of biology.

Introduction

In a broadest sense, the self-assembly and the self-organization via noncovalent interactions must play an important role in critical areas as genetic code, biological information storage, transfer biomolecule (protein, DNA, RNA, etc.) synthesis, and so on. The formation of duplex DNA from its single-stranded constituents, the stabilization of the high-ordered haipirins loops in RNA, and the functional self-assembly of protein-nucleic acid complexes are a result of a large collection of intermolecular forces. These forces include hydrogen bonding, aromatic n-stacking, charge interactions, van der Waals forces, or hydrophobic effects. Moreover, the high fidelity observed in these self-assembled biomacromolecular architectures is largely caused by the high selective molecular recognition processes of natural base-pairing interactions via Watson-Crick H-bonding or of specific protein folding via amide H-bonding, and so on. Among these systems, the nucleobases (1-5) and the nucleosides (6, 7) as well as DNA or RNA (8-10) are well-known, fascinating compounds with a high ability to form controlled multiple intermolecular H-bonding of complementary nature, -C-H-O, hydrophobic, and stacking interactions.

The adenine-uracil interaction that involves two hydrogen bonds (Ka ≅ 102 M-1/CDCl3) is weak and nonspecific compared with the guanine-cytosine interaction, which involves three hydrogen bonds (Ka ≅ 103-105 M-1/CDCl3) that are usually paired via Watson-Crick interactions (4, 5). Homopairing and heteropairing of adenine-uracil and guanine-cytosine derivatives, which result in the formation of interconverting dimers, trimers, and oligomers via the combination of H-bond pairings, seem inadequate to function in any predefined recognition scheme. Amazingly, a very diverse set of interconverting supramolecular entities (oligomers) may be generated by using only these four nucleobases.

Their remarkable self-association properties, via Watson-Crick and Hoogsteen pairing, play a critical role in the stabilization of higher-order RNA haipirins loops, double or triple helix DNA, and G-quartets or G-quadruplexes (3-6). Even though the Watson-Crick (WC) base-pairing is prevalent in natural systems, other H-bonding motifs are present in natural and artificial systems; these motifs include: reverse Watson-Crick (rWC), Hoogsteen (H), reverse Hoogsteen (rH), Wobble (Wo), or reverse Wobble (rWo) (4, 5).

During the last decades, several studies reported the preparation of synthetic discrete supramolecular assemblies (4-8), polymers (1-9), and hybrid materials (10-12) that possess bases of nucleic acids as side groups or chain-end, which are used as precursors to conceive self-organized hybrid materials at nanometric scale.

Nanosized supramolecular materials have received increasing attention during the last two decades (15-19). The supramolecular synthesis provides a powerful tool for the noncovalent generation of such functional supramolecular architectures (15). The supramolecular polymers offer solutions for material molding at the macroscopic level, but their manipulation at the molecular (supramolecular) and nanoscopic levels is still difficult to controll (16). This finding represents a nice extension from material science to biologically interesting component molecules such as nucleic acids that could be of interest for complementary binding (sensing) of nucleic acid strands.

For all these reasons, this article will highlight some recent accomplishments in the field of self-organized hybrid materials, and it will focus on the evolution of discrete nucleobase derivatives from self-assembled dynamic libraries of different devices exchanging in solution to constitutional functional hybrid solid materials. The primary purpose of this review is to describe our recent work on nucleobase-based self-organized hybrid materials. The article begins by describing some recent advances in the area of hybrid supramolecular materials. Then, constitutional dynamic amplification of supramolecular architectures will be examined with particular emphasis on self-organized nucleobase-type systems, presenting combined features of structural adaptation in a specific hybrid nanoenvironment (11). The last part will emphasize the assembly behavior of G-quadruplex superstructures (6, 7) and the transcription of structural information in hybrid materials of functional complexity (12). The final structures of the hybrid materials develop solely from a balance of thermodynamic and kinetic factors as opposed to an iterative processing on a ribosome.

Hybrid Supramolecular Materials

Hybrid organic-inorganic materials produced by sol-gel process are the subject of various investigations, which offer the opportunity to achieve nanostructured materials first from robust organogel systems or second from self-organized supramolecular silsesquioxane systems (16-19). These compounds reveal great potentialities as well on the level of their chemical composition or organization as to that of the concerned applications (16, 17). Of special interest is the structure-directed function of biomimetic and bioinspired hybrid materials and control of their build-up from suitable units by self-organization. Our main interest is on the functional biomimetic membranes in which the recognition-driven properties could be ensured by a well-defined incorporation of receptors of specific molecular recognition and self-organization functions, which are incorporated in a hybrid solid dense or the mesopourous materials (18, 19). A renewed attention for these systems was generated by intriguing proposals that use molecular recognition and self-assembly for the construction of new functional hybrid nanomaterials (20-34).

Many groups, including our own, have found new methods for the elaboration of such self-organized nanomaterials by sol-gel process (10-23). Shinkai and co-workers (10, 18) made an important advancement and they provided useful insights in this field by using organogels that act as robust macrotemplates during sol-gel process on their supramolecular surface. Silsesquioxane-based precursors, in which the functional organic and siloxane inorganic groups are linked covalently, are employed extensively for the controlled generation of self-organized materials. Rigid aromatic molecules (9), which are urea H-bonding ribbons (20-23), are used to transcribe a supramolecular self-organization in a siloxane matrix by a sol-gel process.

Despite such impressive progress, considerable challenges still lie ahead and the more significant one is the “dynamic marriage” between supramolecular self-assembly and the polymerization process, which might communicate kinetically and sterochemically to converge to supramolecular self-organization and functions in hybrid materials. The weak supramolecular interactions (H-bonds, coordination, or van der Waals interactions, etc.) that position the molecular components to give the supramolecular architectures are typically less robust than the cross-linked covalent bonds formed in a specific polymerization process. Accordingly, the sole solution to overcome these difficulties is to improve the binding (association) efficiency of molecular components that generate supramolecular assemblies. At least in theory, an increased number of interactions between molecular components and the right selection of the solvent might improve the stability of the templating supramolecular systems, which communicate with the inorganic siloxane network (35).

Hybrid supramolecular polymers may be divided into two partially overlapping classes: 1) Supramolecular polymers are formed by spontaneous polyassociation of many monomers into the large polymeric architectures via noncovalent interactions (H-bonding, van der Waals, metal ion-coordination, etc.) or reversible covalent bonds and 2) Supramacromolecular polymers resulted from intermolecular self-organization of molecular components during a polymerization process or by molecular recognition of polymeric backbones bearing self-assembling functional groups (Fig. 1).

Three heteroditopic nucleobases-type silsesquioxanes ASi, USi, GSi receptors have been reported by our group recently (Fig. 2) (11, 12). They generate self-organized continual superstructures in solution and in the solid state based on three encoded features: 1) specific molecular recognition, 2) the supramolecular H-bond directing interactions, and 3) covalently bonded triethoxysilyl groups that allow by sol-gel processes to transcribe the solution self-organized dynamic superstructures in the solid heteropolysiloxane materials.

Figure 1. (a) Supramolecular 1 and supramacromolecular 2 polymers resulted from intermolecular and intermacromolecular self-organization. (b) cross-linking and multiple outputs generation after the polymerization of monomers in supramacromolecular polymorfs (11).

Figure 2. Molecular structures of nucleobase ureido-silsesquioxanes ASi, USi, and GSi.

Constitutional Self-Organization of Adenine-Uracil-Based Hybrid Materials

As suggested in the introduction, the nucleobase building blocks generate a very complex dynamic pool of oligomeric ribbon-type or cyclic supramolecular architectures that exchange in solution when simple molecular precursors are used (Fig. 3).

The ASi and USi molecules were designed as rigid H-bonding modules. For instance, by introducing bulky blocking alkoxysilanepropylcarboxamide groups in N9 (A) and N1 (U) positions, we limit only the Watson-Crick and the Hoogsteen interactions as preferential H-bonding motifs. The ASi and USi precursors generate self-organized superstructures based on two encoded features: 1) they contain a nucleobase moiety that can form ribbon-like oligomers via the combination of H-bond pairings; 2) the nucleobase moiety is bonded covalently to siloxane-terminated hydrophobic groups packing in alternative layers.

The dynamic self-assembly processes of such supramolecular systems (Fig. 3) that undergo continous reversible exchange between different self-organized entities in solution may in principle be connected to a kinetically controled sol-gel process to extract and to select an amplified supramolecular device under a specific set of experimental conditions. Such “dynamic marriage” between supramolecular self-assembly and in sol-gel polymerization processes that might communicate sinergistically leads to “constitutionnally-driven hybrid materials.” Based on this structural information and on the crystal structures of similar alkylnucleobase derivatives, the relative arrangement of molecules of ASi and USi in powders and in the MA, MU and MA-U hybrid materials is similar to analogous ureidocrown-ether (20-23) and ureidoarene (36) superstructures. The generation of hybrid materials MA, MU, and MA-U can be achieved using mild sol-gel conditions. In a typical procedure, we have prepared solutions of precursors A, U, or an equimolar mixture of A:U (1:1, mol/mol) in acetone, then we added deionized water and benzylamine as a catalyst. The mixture was kept at room temperature under static conditions for 15 days. The solvent was then evaporated at room temperature to yield the hybrid materials MA, MU, and MA-U as the white powders.

Figure 3. Supramolecular dimers, trimers, and oligomers generated by H-bonding self-assembly of (a) adenine, (b) uracil, and (c) adenine-uracil base-pair. (R = sugar, alkyl, etc.)

The X-ray powder diffraction (XPRD) experiments presented in Fig. 4 show that well-defined, long-range order is present in the precursors ASi and USi. The long-range order is less pronounced than in the precursor materials in the hybrid materials MA, MU, and MA-U after the sol-gel step: less well-defined peaks are present than for the precursor and the average peak width increases, which indicates smaller domains in which coherent scattering occurs (37).

The small angles XRPD pattern of the precursor A presents two well-resolved Bragg diffraction peaks that correspond to two crystallographycally distinct phases: (A)nWC-H and (A)nH oligomers (Fig. 4a). A freshly synthesized solid sample of A is crystallized predominantly as Watson-Crick-Hoogsteen (A)nWC-H oligomer. A second nonpredominant polymorph of the all-Hoogsteen (A)nH oligomers are present in powder as a result of breaking of Watson-Crick H-bonds and of creating the new Hoogsteen H-bonds (38). The small angles XRPD pattern of hybrid material MA presents a unique, well-resolved Bragg diffraction peak (Fig. 4a), which corresponds to a crystallo-graphically distinct and unique all-Hoogsteen phase: (A)nH.

Figure 4. Constitutional (a) Hoogsteen packing of the Adenine MA hybrid material; (b) Watson-Crick packing of the Uracil MU hybrid material, and (c) A2WCU2H packing of the Adenine-Uracil MA-U hybrid material.

Adenine (39) 9-methyladenine (40) and 9-ethyladenine (41) crystallize through the formation of unique Hoogsteen H-bonds in two-dimensional layers. These layers, which are stratified alternatively, exhibit two types of interfaces in between: one contact surface because of the π-π stacking of adenine tapes and other surface that results from hydrophobic interactions of alkyl groups, which are in van der Waals contact. Similarly, the structure of the (A)n oligomers is most likely dictated by hydrophobic interactions between the grafted ethoxysilanepropyl-carboxamide groups (Fig. 5b). In a freshly prepared A sample, the solvent logged between hydrophobic groups favors the extended (A)nWC-H oligomers. The condensation process between the ethoxysilane groups during the sol-gel process do favor the more compact (A)nH oligomers in which the hydrophobic groups are interlocked, which stabilizes the interaction between Hoogsteen H-bonded layers.

The small angles XRPD patterns of the precursor U as well as of the hybrid material MU present one Bragg diffraction peak (Fig. 4b), which corresponds to a characteristic Watson-Crick (U)2WCdimer. The two other possible structures, the reverse Watson-Crick dimer (U)2rWC and the quartet (U)4 (see Fig. 3), do not correlate with the experimental distance.

A freshly evaporated solid sample of an equimolecular mixture in acetone of A and U presents two Bragg diffraction peaks that correspond to A2WCU2H and A2HU2WC oligomers, respectively. The small angles XRPD pattern of the hybrid material MA-U presents a unique Bragg diffraction peak that corresponds to a characteristic interplanar distance of A2WCU2H oligomer (Fig. 4c). Amazingly, the unique structure of the resulting hybrid material MA-U that corresponds with experimental results is consistent with the formation of the Hoogsteen base pairing between Uracil and Adenine and with the formation of the Watson-Crick base pairing between two adenine molecules. Early contributions by Etter et al. (42), Castellano et al. (43), and others have been confirmed recently by Zimmermann calculations (44) for nearly exclusive preference for Hoogsteen binding, inside the classic A+U base-pairing, within 1:1 base-pairing complexes between alkyladenine and alkylthymine derivatives. Factors that contribute to the preference for Hoogsteen geometry are the shorter CH—O contacts, which is a favorable alignment of the dipoles and is a greater distance between secondary repulsive sites (43, 44). Although many have recognized that in the solid state, the uracil or thymine preferentially bind adenine through Hoogsteen binding; therefore, this result is particularly interesting because the A2WCU2H oligomer is amplified quantitatively from a dynamic pool of oligomers in solution via sol-gel transcription.

As a general rule, which is proved by the differences between the values of interplanar Bragg diffraction distances, the condensation process between the ethoxysilane groups during the sol-gel process results in the formation of the more compact hybrid materials MA, MU, and MA-U compared with the unpolymerized A, U, and AUmix powders (Fig. 5).

Nucleobase oligomerization by H-bonding can be an advantageous choice to reinforce the controlled communication between interconnected “dynamic supramolecular” and “fixing siloxane” systems. Moreover, the hydophobic interactions can play an important role to stabilize compact packed superstructures that may be “extracted selectively” under the intrinsic stability of the system or external stimuli by polymerization in solid state.

Figure 5. Toward a constitutional transcription of base-pairing codes in hybrid materials: (a) Guide to the eye interplanar dSi-Si distances calculated from the geometry of minimized structures versus experimental interplanar Bragg diffraction distances. The squares correspond to the unpolymerized powders of precursors A, U, and their 1:1 mixture AUmix, whereas the circles correspond to hybrid materials MA, MU, and MA-U. b) Postulated model of self-organization of parallel H-bonded nucleobase aggregates and hydrophobic propyltriethoxysilane layers.

Amplification and Transcription of the Dynamic Supramolecular Chirality of the G-Quadruplex

G-quartets are formed by the hydrogen bonding self-assembly of four guanosine and are stabilized by alkali cations. They play an important role in biology and in nucleic acid telomers in particular, which are of potential interest to cancer therapy (6, 7). The role of cation templating is to stabilize by coordination to the eight carbonyl oxygens of two sandwiched G-quartets: the G-quadruplex is the columnar device formed by the vertical stacking of four G-quartets.

The G-quartet architecture represents a nice example of dynamic supramolecular system that has been used as building block for gelators (45), columnar polymeric aggregates (46), self-organized surfaces (47), prototypes of chemical dynamic devices (48), and so on.

In the last decades, G-quartets (6) and a similar folic acid quartet (49) have been proposed as powerful scaffolds for building synthetic ion channels. Although stable in organic solvents, they do not seem to have defined transport functions in hydrophobic membranes. Barrel-stave-, lipophilic-calix(4)arene-8-aromatic-guanosine conjugates have been used to stabilize the formation of G-quartets (7). Very recently, new strategies based on reversible metathesis were used successfully by Kaucher et al. (50) to generate a rich array of interconverting ion-channel conductance states of a unimolecular G-quartet in a phospholipid membrane. Polymeric guanosine hydrogels that can be interconverted reversibly between gel and sol states may be used to synthesize adaptative functional nanostructures (45).

Despite such impressive progress, considerable challenges still lie ahead, and the more significant challenge is to improve the stability of G-quartet dynamic aggregates in polymeric devices such as films or membranes to extend (address) the transport studies at macroscopic level. Several studies reported the preparation of discrete supramolecular assemblies of nucleobases. However, the “dynamic communication” between the supramolecular self-assembly of nucleobases and the polymerization processes, which kinetically and sterochemically might communicate, is not so trivial.

On the other hand, the G-quadruplex with a twisted supra molecular architecture represents a nice example of a dynamic chiral supramolecular system, when guanine and guanosine molecules are used. Molecular chirality may be used as a tool to assemble molecules and macromolecules into supramolecular structures with dissymmetric shapes. The supramolecular chirality, which results from both the properties and the way in which the molecular components associate, is by constitution dynamic and therefore examples of large-scale transcription of such virtual chirality remain rare.

For all these reasons, the guanine building blocks and the sol-gel chemistry were used as molecular precursor to conceive hybrid chiral materials at nanometric and micrometric scales. Our efforts involved the synthesis and the self-assembly of a guaninesiloxane monomer GSi (Fig. 3) in the G-quartet and G-quadruplex supramolecular architectures (Fig. 6), which are fixed in a hybrid organic-inorganic material by using a sol-gel transcription process, followed by a second inorganic transcription in silica, by calcination.

Figure 6. (a) The cation-templated hierarchic self-assembly of guanine alkoxysilane gives the G-quartet and the G-quadruplex (b) transcribed in solid hybrid materials by sol-gel in the presence of templating K+cation.

The generation of G-quadruplex hybrid material can be achieved by mixing GSi derivative with potassium triflate in acetone, followed the sol-gel process performed at room temperature using benzylamine as catalyst. Then, the hybrid materials were calcined at 400° C to transcribe their superstructural features into inorganic silica replica materials.

We have observed a long-range amplification of the G-quadruplex supramolecular chirality into hybrid organic-inorganic twisted nanorods followed by the transcription into inorganic silica microsprings (12). We believe that in the first sol-gel step, the polycondensation reactions of the inorganic alkoxysilane network take place around tubular twisted superstructure of G-quadruplex. The dynamic G-quadruplex is fixed in a covalently bonded siloxane network, and the structural (constitutional) memory of G-quadruplex is transcribed in the hybrid materials. These fixed (“frozen”) objects are chiral and self-correlate with a hexagonal order to generate anisotropic mesophases interconnected via condensed siloxane bridges. We obtained by sol-gel process a hybrid material that features a twisted hexagonal rod-like morphology of about 2 pm length and 350-850 nm diameter (Fig. 7). The mixture of these entities contains left and right twisted nanorods, which are a result of the nonpreferential dissymmetric orientation of the G-quartets. They are chiral, and no inversion centers have been observed within the same entity. Amazingly, these materials are at nanometric or micrometric scale topologically analogous to its G-quadruplex supramolecular counterpart. Similar “communication processes” have been identified in the DNA transcription into inorganic materials (10).

Figure 7. (a) Scanning electronic microscopy images of the left- and right-hand twisted hexagonal nanorods resulted by sol-gel transcription of the chiral hexagonal G-quadruplex in the hybrid organic-inorganic material, (b) crystal structure of G-quadruplex in space filling representation, and c) hexagonal crystal packing from published crystallographic data (12).

After the sol-gel process, the preformed helical silica network has embedded probably enough chiral information to be amplified (reinforced) irreversibly during the calcination process when almost total condensation of Si-OH bonds occurs. By calcinations of the hybrid material, the templating twisted G-quadruplex architectures are eliminated, and inorganic silica anisotropic microsprings are obtained. They present the same helical topology, without inversion inside the helix. These objects have a different helical pitch, which depends strongly on the self-correlation between hexagonal twisted mesophase domains at the nanometric level.

Our findings showed a new way to transcribe the supramolecular chirality of a dynamic supramolecular architecture; the transfer of the supramolecular chirality of G-quadruplex at the nanometric and micrometric scale is reported, thereby creating nanosized hybrid structures or microsized inorganic superstructures, respectively. Moreover, we obtain chiral materials by using a starting achiral guaninesiloxane GSi as precursor of achiral G-quartet and of chiral supramolecular G-quadruplex. Figures 7 and 8 represent the first pictures of the dynamic G-quadruplex transcribed at the nanometric level.

Finally, our results show a new way of embedding supra molecular chirality in materials, which is of interest for the development of a supramolecular approach to nanoscience and nanotechnology toward systems of increasing functional complexity.

Figure 8. Scanning electronic microscopy images of silica microsprings resulted by calcination of hybrid nanorods.

Conclusions

The nanometric or the micrometric transcription of the supra molecular functional devices, although marked significant achievements, represent a young field. Whereas many elegant functional systems based on nucleobases self-assembly have been prepared in recent years, it is almost clear that the synthetic efforts might be developed to extend and to understand the key features of such self-organized systems and the nanometric and micrometric levels. As importantly, this work established that molecular precursors could be used to affect molecular recognition and self-assembly that differ from those found in typical biological DNA and RNA systems. Nanometric self-organization using molecular nucleobases is clearly different from biological nucleotide self-assembly. These initial hybrid nanomaterials presented in this paper paved the way to the development of new functional macroscopic materials that contain nucleobases as structural building blocks.

Some systems can be applied in the areas of ionic, electron, and energy transport studies (9) and in sensing technology. Finally, our results show a new way of embedding nucleobases self-assembly and supramolecular chirality of G-quadruplexes in hybrid materials, of interest for the development of a supramolecular approach to nanoscience (51). Likewise, the hybrid polymeric arrays with nucleobases functionalities represent an area where the best is surely best to came; it unlocks the door to the new materials world paralleling that of biology.

Acknowledgment

This work, which was conducted as part of the award “Dynamic Adaptative Materials for Separation and Sensing Microsystems” made under the European Heads of Research Councils and European Science Foundation EURYI (European Young Investigator) Awards scheme in 2004, was supported by funds from the Participating Organizations of EURYI and the EC Sixth Framework Programme. Seewww.esf.org/euryi.

I thank the past and the present members of my laboratory with whom we have collaborated in these studies: Carole Arnal-Herault, Mathieu Michau, Andreea Pasc, Arie van der Lee, Eddy Petit and Didier Cot.

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Further Reading

Gomez-Romero P, Sanchez C. Functional Hybrid Materials. 2004. Wiley-VCH, New York.

Lehn J-M. Supramolecular Polymers Chemistry — Scope and Perspectives, 2nd ed. Ciferi A, ed. 2005. CRC Taylor and Francis, Boca Raton, FL. pp. 3-27.