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ABSTRACT
Lanreotide, a synthetic, therapeutic octapeptide analog of somatostatin, self-assembles in water into perfectly hollow and monodisperse (24-nm wide) nanotubes. Lanreotide is a cyclic octapeptide that contains three aromatic residues. The molecular packing of the peptide in the walls of a nanotube has recently been characterized, indicating four hierarchical levels of organization. This is a fascinating example of spontaneous self-organization, very similar to the formation of the gas vesicle walls of Halobacterium halobium. However, this unique peptide self-assembly raises important questions about its molecular origin. We adopted a directed mutation approach to determine the molecular parameters driving the formation of such a remarkable peptide architecture. We have modified the conformation by opening the cycle and by changing the conformation of a Lys residue, and we have also mutated the aromatic side chains of the peptide. We show that three parameters are essential for the formation of lanreotide nanotubes: i), the specificity of two of the three aromatic side chains, ii), the spatial arrangement of the hydrophilic and hydrophobic residues, and iii), the aromatic side chain in the β-turn of the molecule. When these molecular characteristics are modified, either the peptides lose their self-assembling capability or they form less-ordered architectures, such as amyloid fibers and curved lamellae. Thus we have determined key elements of the molecular origins of lanreotide nanotube formation.
INTRODUCTION
Self-assembly is characterized by spontaneous diffusion and specific association of molecules dictated by noncovalent interactions. It can be biologically inspired given that the cells contain numerous functional nanostructures built from molecular self-assembly, such as membranes, actin filaments, tubules, chromosomes, flagella, and cytoskeleton. But self-association processes are also essential during biological processes such as protein folding, molecular recognition, and enzyme-substrate binding.
The key elements of molecular self-assembly are a complementary shape between the individual components and weak noncovalent interactions. For biological materials, these noncovalent interactions are typically hydrogen bonds (intra- and intermolecular and with water), ionic bonds, hydrophobic effects, and electrostatic and van der Waals interactions. Although many of these interactions are weak (<5 kcal/mol), their large numbers make the final architectures highly stable. Another consequence of these types of interactions is the possibility of rapid exchange between a molecule involved in the architecture and an external molecule in solution. This implies that the...