Cyclic peptides

Self-assembling NTs based on a variety of cyclic peptides have been reported. A well-characterized example is the naturally occurring Lanreotide growth hormone inhibitor peptide (fig 7a ). When dissolved in water, it adopts a closed compact β-hairpin-like conformation through a disulphide bond (fig 7b). At a peptide concentration of 3–20% wt/wt, a gel is formed. In these conditions, self-assembly into a bilayer is observed, consisting of amphiphilic β-sheets with systematic segregation of aromatic and aliphatic side chains. Thus, the hydrophobic effect generates a bilayer, while intermolecular backbone hydrogen bonding causes assembly of peptides in one dimension into long ribbons. Finally, the hydrophobic effect between the edges of the ribbons stabilizes lateral association of 26 ribbons to form the wall of the nanotube (fig 7c). This process gives rise to hexagonally packed, highly monodisperse long NTs with a diameter of 24.4 nm and a wall thickness of 1.8 nm (fig 7d – f).

Fig. 7. Lanreotide-acetate peptide nanotubes in water. (a) The molecular structure is a β-hairpin conformation stabilized by the disulfide bridge. (b) One-dimensional self-assembly of a ribbon made of two stacked β-sheets. (c) Lateral assembly of 26 ribbons to form a nanotube. (d) Liquid-crystalline hexagonal columnar phase. (e) Freeze-fracture electron micrographs of a 14% wt/wt sample, perpendicular, and (f) parallel to the direction of the nanotubes.

By far the most extensive literature on cyclic peptide NTs is devoted to the molecules designed in Ghadiri's laboratory. These cyclic peptides have an even number of alternating D and L amino acids, and stack through extensive intermolecular hydrogen bonding to form long cylindrical structures with an anti-parallel β-sheet structure. The outer surface of NTs is defined by all the amino acid side chains and thus can be controlled by peptide design, or by covalent incorporation of polymers, producing polymer shells around the NTs (fig 8). The ability to tune the outer surface properties enables NT formation in a variety of different environments, such as in bulk solution, in the solid state (crystals of regularly packed nanotubes), and as transmembrane pores inside the cellular lipid bilayer that can act as efficient ion channels. The pores can be preferentially assembled inside bacterial rather than eukaryotic cell membranes and cause bacterial death through osmotic collapse. This work has led to the development of new antimicrobial and cytotoxic agents, controlled-release drug delivery carriers, and new artificial ion channels whose transport properties are tuned by peptide design. The internal diameter of these NTs is completely uniform and can also be adjusted by peptide design. Systematic studies reveal that cyclic octapeptides exhibit good rigidity and predisposition for tubular assembly with a van der Waals internal diameter of 7 Å and can transport K⁺ and Na⁺ across the lipid bilayer. A cyclic decapeptide NT possesses a 10 Å van der Waals internal diameter and transports larger molecules such as glucose, while the smaller octapeptide lacks such activity. A cyclic dodecapeptide NT has an internal van der Waals diameter of 13 Å.

Fig. 8. Grafting a polymer shell on preassembled cyclic peptide tubes: D,L-Cyclo-α-peptides carrying initiator groups stack to form tubular structures from which N-isopropylacrylamide (PNIPAM) is grown by atom-transfer radical polymerization (ATRP); HMTETA=1,1,4,7,10,10-hexamethyltriethylene. AFM images depict the peptide-PNIPAM hybrids (scales: 2 mm and 800 nm).

Non-biological applications of the NTs have also been examined. Elucidation of the electronic properties of these nanotubes suggests a wide highest occupied molecular orbital–lowest unoccupied molecular orbital (HOMO-LUMO) gap for the nanotubes, of interest to bioelectronic device applications. Unmodified peptides are electronically insulating as are most biomaterials made of natural amino acids. In a recent study, cyclic peptides have been designed bearing four cationic 1,4,5,8-naphthalenetetracarboxylic groups (NDI). These molecules undergo redox-triggered self-assembly in aqueous solution into long peptide NTs that possess highly delocalized electronic states. The cyclic peptide assembly here is used as a scaffold to promote stacking of NDI groups and charge transfer between them and to provide ordered electronically active biomaterials with potential utility in optical and electronic devices.

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