Info

Stacks of Helical Strands and Macrocycles

Whereas in the case of peptide assemblies based on coiled-coil helices the interaction is mainly controlled by hydrophobic contacts, also hydrogen bonding can be exploited to drive hybridization. In Nature this principle is found e.g. in Gramicidin A, a channel forming linear 15-residue a-peptide composed of alternating d/ l-amino acids (more on Gramicidin A can also be found in Section 2.4.1 of Chapter 2). This alternation in the absolute configuration of the amino acids prevents the formation of a normal a-helix; instead a more open b-helix with an inner pore is formed. Two such helices then self-assemble within the cell membrane into a head-to-tail dimer held together by intermolecular H-bonds at the dimerization interface. Through the inner pore of this dimer, ions can then pass through the membrane [3]. The same principle was adopted by Ghadiri [29] and coworker, who designed self-assembling cyclic peptides with alternating d/l-configuration (Fig. 4.7). For example these eight-residue cyclic peptides have flat, ring-shaped conformation and their backbone amide functionalities are perpendicular to the side chains and the plane of the ring structure. This conformation leads to an intermolecular stacking via H-bonds to form nanotubes, which can also serve as pores for ion transport when embedded into a lipid membrane. Tailor-made pep-tide nanotubes can be achieved by variation of the side chains. Their surface-exposed arrangement leads to a membrane selectivity, which can be applied in antibacterial agents that cause rapid cell death by increased cell wall permeability and collapsed transmembrane ion transport.

Fig. 4.7 Two helices of Gramicidin A, a 15-residue «-peptide composed of alternating D/L-amino acids (A), form a stacked dimer within a membrane allowing for ion transport though the central pore (B). Cyclic peptides with alternating D/L-configuration (C) can form self-assembled nanotubes via intermolecular hydrogen bonding (D) [29].

Fig. 4.7 Two helices of Gramicidin A, a 15-residue «-peptide composed of alternating D/L-amino acids (A), form a stacked dimer within a membrane allowing for ion transport though the central pore (B). Cyclic peptides with alternating D/L-configuration (C) can form self-assembled nanotubes via intermolecular hydrogen bonding (D) [29].

Another Gramidicin A analog was introduced by Guichard [30] et al. They synthesized a cyclic oligourea with homochiral residues, which self-assembles in the crystalline state via H-bonding between the urea units. Within the crystal these polar nanotubes are held together by loose van der Waals contacts. A cyclic peptide assembly with hydrophobic cavities was developed by Granja and coworkers [31]. They use 3-aminocyclohexylcarboxylic acid (g-Acc-OH) alternating with d-a-amino acids to obtain a conformation of a flat peptide backbone with perpendicular arranged amide functionalities (Fig. 4.8). All b-methylene groups of the cyclo-hexane rings point into the interior of the cyclic peptide, which leads to a cavity with a partial hydrophobic interior. Modifying the C2 of g-Acc-OH might lead to peptide nanotubes with functionalized inner surfaces.

Also the conformational preference of fused heterocycles can be exploited for helix formation (Fig. 4.9 A), as Lehn [32] et al. could already show a couple

Fig. 4.8 (A) Crystal structure of Guichard's oligourea based cyclic peptide [30]; (B) structural motif of the g-Acc-OH based cyclic peptide designed by Granja [31].

of years ago. 2,2 '-Bipyridines and related heterocycles adopt a transoid conformation due to repulsive dipole-dipole interactions which can be exploited to bias an oligomer towards helix formation. In this context, it was recently shown that by using naphthyridines instead of pyridines an opening of the structure results,

A transoid conformation

Fig. 4.9 Helical oligoamides (A) can also further interact with other small molecules. Alkali metal cations can induce the formation of large supramolecular helices from small springs which do not self-assemble by themselves (B) [32].

which allows now the inclusion of other molecules within the central pore of the helix: A first step towards helical channels [33]. For example, the naphthyridine pyrimidine oligomer (n = 2) in solution (CDCl3/CD3CN) adopts a conformation representing a single helical turn. In the presence of alkali metal ions such as Cs+ a supramolecular association of such individual helical springs occurs leading to long hollow tubes, in which, as the authors suggest, cations are incorporated. It is only this mutual interaction of two springs with one cation that stabilizes these supramolecular aggregates, as in the absence of cations only monomeric springs were observed (Fig. 4.9 B). The formation of such cation channels is also supported by electrospray-mass spectrometry and transmission-electron microscopy studies.

0 0

Post a comment