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Applications of Foldamer Hybridization

One reason for self-assembly has already been pointed out in the beginning. Through the noncovalent interaction of smaller building blocks, more complex structures are obtained which display properties not present in the underlying molecules themselves [1, 2, 3, 6]. Hence, supramolecular synthesis provides an alternative approach to more complex systems besides covalent chemistry. The synthesis of smaller building blocks which then self-assemble to produce the desired structure can be easier, less challenging and more economical than to directly synthesize one large molecule with the same properties. An illustrative example is the leucine zipper described in the beginning. Only the synthesis of one peptide is needed which then spontaneously self-assembles to form the Y-shaped dimer with the DNA binding site in the junction. Rather complex structures can thus be obtained from rather simple building blocks [17].

Another even more important aspect of hybridization is information storage and transfer! As had already been pointed out before, hybridization is often very specific if e.g. controlled by H-bonds. This means, that the sequence (e.g. the pattern of H-bond donors and acceptors) of one strand completely determines the sequence of the second strand with which hybridization can occur. This holds both for homodimerization and for heteroduplex formation [14b]. If not the structure but rather the information itself is important, hybridization thus offers a way for safely storing and also reproducing this information. This is what the DNA double helix is for. The linear sequence of the strand contains the genetic information needed to produce proteins. The double helix is the storage form for this information. As two complementary strands are present, both with the same information (otherwise they would not hybridize to form a stable double helix) the risk of information loss due to chemical mutations etc. is greatly diminished [74]. There is always at least one safety copy of the genetic information present. Furthermore, when the information needs to be reproduced (as for cell division or protein production), each DNA strand serves as a templating matrix for either a new DNA strand or a mRNA. Thus the specificity of the hybridization pattern ensures correct information transfer. Nature uses this property of hybridization since the beginning of life most likely [16].

Of course chemists have strived to find artificial systems that also allow a controlled and selective reproduction of information encoded in the sequence of a

Fig. 4.27 Schematic representation of an autocatalytic self-replication cycle based on a self-complementary template AB' and two monomers A and B'.

linear polymer. The initial break throughs were obtained with self-replicating nucleotides by Orgel [75] or von Kiedrowski [76]. An oligonucleotide serves as a template to assemble mononucleotides as dictated by the correct Watson-Crick base pairing pattern (Fig. 4.27). An enzyme-free chemical ligation then stitches the mononucleotides together to produce an oligonucleotide with a complementary sequence to the initial coding strand. If the initial oligonucleotide is composed of a self-complementary sequence, the product can also serve as a new template for the next cycle, hence, an autocatalytic system results.

Lateron also self-replicating peptides were designed for example by Ghadiri [77] or Chmielewski [78]. Ghadiri used a leucine zipper motif based on the GCN4 transcription factor. Small heptapeptide segments, which represent the repeating heptad unit of the leucine zipper, were aligned by a larger peptide template and then chemically ligated to produce a copy of the templating peptide strand. Again an autocatalytic self-replicating system resulted (Fig. 4.28). A rather major disadvantage of such systems is of course product inhibition, which reduces the catalytic turnover number. The final product strand forms a more stable complex with the initial template strand than the smaller peptide segments.

A bimolecular complex in general is more stable than a trimolecular one due to entropic reasons. Hence, to increase the autocatalytic efficiency and to approach exponential growth various modifications have been introduced into the initial self-replicating peptide systems such as the use of shorter peptides to destabilize the coiled-coil product and hence to facilitate its dissociation at ambient temperature. Also a proline-kink in the middle of the template strand can help to destabilize the coiled-coil product, whereas the two short peptide segments before liga-tion can bind to the either side of the kink without much problem. Recently, also

Fig. 4.28 Schematic presentation of a reaction cycle for a self-replicating peptide system. A template strand binds two smaller peptide fragments as dictated by the correct hybridization pattern. Chemical ligation of the two fragments then leads to another copy of the template even though real exponential growth as expected for such an autocatalysis is often hampered by product inhibition.

Fig. 4.28 Schematic presentation of a reaction cycle for a self-replicating peptide system. A template strand binds two smaller peptide fragments as dictated by the correct hybridization pattern. Chemical ligation of the two fragments then leads to another copy of the template even though real exponential growth as expected for such an autocatalysis is often hampered by product inhibition.

a self-replicating peptide/RNA system was designed which is based on the cross-hybridization between a RNA aptamer and a linear peptide strand [79]. The RNA aptamer was rationally cut into two halves and modified at each end to allow chemical re-ligation. The peptide strand as a template then binds the two halves of the aptamer, pre-orientates them and hence facilitates their re-ligation.

In a modification of this principle of self-replication, duplex formation between two complementary oligonucleotides can also be used to control a chemical reaction between more or less any two chemical entities A and B which can be attached to two hybridizing oligonucleotides. Duplex formation then brings the two reactants A and B into close proximity thereby increasing their effective molar concentration relative to the situation in free solution and thus enabling a chemical reaction between them. This so called DNA-templated synthesis has been advocated in recent years mainly by Liu and coworkers [80]. In various experiments they investigated the use of different oligonucleotide architectures for amine acylations, Wittig olefinations, 1,3 dipolar cycloadditions and reductive aminations and a variety of other reactions. The advantage of such DNA tem-plated reactions compared to their counterparts in free solution is the control of selectivity. Only those two partners can react that are attached to the correct complementary strands as the reaction only occurs within the hybridized duplex strand (Fig. 4.29 A). For example, as much as 12 different reactants with normally incompatible chemical functionalities selectively form only 6 products if the reac-tants are attached to different but mutually complementary oligonucleotide sequences.

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