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Introduction

In Nature, the function of a molecule often requires a specific shape and structure which control or even first enable both its physical properties and also its interactions with other molecules. A most illustrative example are the proteins, linear polymers of amino acids (Fig. 4.1) [1]. Per se such a peptide chain is a rather flexible molecule even though some parts of the conformational space are restricted due to the hindered rotation around the central amide bond. Nevertheless, the resulting three-dimensional (3-D) structure controlled by the covalent framework of the linear peptide strand alone is a random coil at best [2]. However, additional secondary, noncovalent interactions such as H-bonds, electrostatic or hydrophobic contacts between even remote parts of the peptide chain can induce a structural ordering. Parts of the protein first fold into specific secondary structures such as a-helices or b-sheets which then further interact with each other until a fully folded protein with a specific 3-D shape is obtained [3-5]. The correct 3-D structure is vital for the function of the protein. For example, in enzymes only the properly folded state forms the correct active site and hence allows the specific binding and controlled transformation of a substrate [6]. However, even more complex structures can be obtained by the further supramolecular interaction of more than one protein molecule. Again, the resulting overall shape of the aggregate determines its properties. In the case of the protein collagen only a properly folded intertwined triple helical structure formed by the mutual interaction of three peptide strands guarantees the formation of linear fibers with a certain rigidity and stiffness which are needed to build up the extracellular matrix [1].

The folding of a molecule and also its supramolecular interactions with another molecule are controlled by weak and reversible noncovalent interactions. Therefore, structure formation is a dynamic equilibrium process which depends on the number and specific nature of these interactions as well as external parameters (e.g. solvent, temperature). For example, stable a-helices are formed from a-amino acids only with chain lengths of approximately more than 10 amino acids.

Fig. 4.1 Schematic representation of the different levels of structural order in a protein. The correct function is directly depending on the proper fold of the protein (reprinted with permission; copyright Prentice Hall).

In shorter chains the noncovalent interactions responsible for helix-formation are not strong enough to compensate the unfavorable entropy change associated with the folding of the flexible molecule [3]. Furthermore, the external addition of large concentrations of guanidinium salts or simply heat can reverse the folding of a protein thereby destroying its function. A denatured enzyme does not have any activity any more. Hence, folding is not only vital for the properties of a molecule but the folding (and in consequence everything depending on the fold) can in principle also be externally controlled [1].

Inspired by this overwhelming importance of molecular shape and structure in Nature, chemists have always been interested in designing molecules with specific 3-D structures; some examples are discussed in Chapters 1-3. In principle there are several ways to induce a specific conformation or fold in a molecule (Fig. 4.2): (i) Steric effects in most often rather rigid molecules can be used to induce certain structures and conformations [7]. Examples are the long known aromatic helicenes [8-10] or the shape-persistent aromatic macrocycles introduced in recent years by Moore [11] or Gong [12] for example. (ii) In flexible molecules

Fig. 4.2 Different possibilities to obtain defined conformations within a molecule: (A) by steric interactions within a rather rigid covalent framework such as in helicenes [8b]; (B) by attractive noncovalent interactions between remote parts of a molecule as in an oligoamide [15a] or (C) by the hybridization induced folding of two or more molecules shown here for a double helix formed from two pyridinedicarboxamide oligomers [33a].

Fig. 4.2 Different possibilities to obtain defined conformations within a molecule: (A) by steric interactions within a rather rigid covalent framework such as in helicenes [8b]; (B) by attractive noncovalent interactions between remote parts of a molecule as in an oligoamide [15a] or (C) by the hybridization induced folding of two or more molecules shown here for a double helix formed from two pyridinedicarboxamide oligomers [33a].

without any built-in biased conformation attractive noncovalent interactions between even remote parts of the molecule can be used to induce a folding as described above for proteins. For such molecules the term "foldamer" has been proposed by Gellman [13]. For example, aromatic polyamides as introduced by Lehn and Huc [33], Gong [14] and Li [15] adopt specific helical shapes due to intramolecular hydrogen bonding and stacking interactions. Flexible oligomers composed of alternating units of electron-rich and electron-poor aromatic as designed by Iverson [55] are another interesting example. (iii) Finally, defined structures can also be achieved not only within one molecule but through a supramolecular interaction of two or more molecules (''hybridization''). The beautiful and fascinating double helical structure of DNA, discovered 1953 by Watson and Crick [16], is one very shining example as well as the structure of collagen already mentioned above. In some cases the individual molecules have a distinct structure even before hybridization more often however at least for artificial systems hybridization induces the 3-D structure of the whole supramolecular assembly while the individual molecules are unstructured.

Whereas examples for the first two approaches can be found in Chapters 1-3, we will describe in this chapter a few instructive examples illustrating the last aspect, the hybridization of foldamers (''foldamer hybrids''). Hence, this chapter deals with in principle flexible molecules that form supramolecular assemblies with a defined composition and structure. Of course, we can not cover all work that has been done in this field. Instead we will demonstrate the basic principles and highlight some general aspects using selected recent examples based both on biological (e.g. peptides and nucleic acids) as well as completely artificial foldamers. The choice of examples is subjective and is not intended to question the importance of other contributions not discussed here. We will first concentrate on fol-damer hybrids in which the monomers by themselves already have a distinct and well characterized structure (Section 4.2). However, at least in most artificial systems the structure of the underlying monomers is not well defined and the aggregation is the trigger for structure formation. Examples of such hybridization induced folding will be discussed in Section 4.3. The focus in both parts will be on the formation of aggregates with a defined composition such as duplexes or triple helices. The formation of even larger aggregates which unfortunately most often are not really well defined in terms of structure and composition will only be briefly mentioned (Section 4.4). Finally, we will discuss some examples how hybridization can also be exploited to achieve certain functions such as information storage and transfer (Section 4.5).

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