Three-dimensional molecular architectures by the controlled self-assembly of $\beta$ -peptide foldamers

Abstract

Molecular self-assembly of organic compounds by multiple noncovalent interactions is recognized as a promising bottom-up method to construct nanoscale materials. In particular, self-assembly of peptide scaffolds has been significantly investigated in order to understand the principle of protein folding and underlying mechanism of self-association of natural counterparts. Functional diversity and inherent biocompatibility of peptides afford a myriad of opportunities for the novel design of versatile nanomaterials. However, most of the precedent studies on self-assembly of natural peptides have displayed limited supramolecular morphologies such as tubes, fibers, sheets, and spheres. And intrinsic conformational flexibility of peptides often makes the assembly process complicated and elusive on a practical level. To extend the diversity of the three-dimensional shapes of self-assembled structures without any incidental complications, one should be able to establish a set of assembling components that can be directly linked to the su-pramolecular morphologies by governing parameters of self-assembly. This dissertation treats the unusual and unprecedented three-dimensional molecular architectures by the self-assembly of non-natural $\beta$ -peptide foldamers. Homo-oligomers of trans-2-aminocyclopentanecarboxylic acid (trans-ACPC) well-known for the stable 12-helical secondary conformations and predictable intermolecular interactions were used as the building blocks of self-assembly. In the aqueous solution of nonionic surfactant pluronic P123, trans-ACPC heptamer and hexamer self-assembled into micron-sized unprecedented structures such as windmills, petals, square rods, and tooth shapes with very uniform shape and size distributions. And the supramolecular morphologies were readily controlled by the regulation of surfactant micelles. Surfactant micelles are considered to recognize the functional anisotropy of trans-ACPC oligomers to enhance or suppress the growth of specific facets. The mechanisms of self-assembly were suggested based on the observed supramolecular shape evolutions. Powder X-ray diffraction patterns and thermal properties of the assemblages were analyzed to verify the molecular arrangements inside the assembled structures. In case of the tooth-shaped assembly of trans-ACPC hexamer, it was revealed that four individual helical monomers constitute a superhelix in a unit cell of the assembly, similar to that found in the supercoiled structure of collagen. In addition, other types of shape evolution in self-assembled structures were observed by adjusting the assembling parameters. A number of polyhedral shapes such as square pyramids, rhombic dodecahedrons, and cuboids were obtained by the self-assembly of trans-ACPC hexamer and heptamer in a presence of ionic surfactant CTAB. These are the first examples of peptide self-assembly which exhibit finite and well-defined three-dimensional supramolecular structures with highly controllable features. The obtained unique three-dimensional molecular architectures were named “foldecture” as a compound of “foldamer” and “architecture”. Interestingly, a series of self-assembled structures of $\beta$ -peptides were aligned in specific orientations by the external strong magnetic field to facilitate the hierarchical organization. The origin of magnetic alignment is thought to be torque generation from the diamagnetic anisotropy in crystal structures. Highly ordered organization of well-defined self-assembled structures of $\beta$ -peptide foldamers not only provides an insight for the higher-order structures found in natural proteins but is expected to be employed to create the anisotropic surfaces for a wide variety of potential applications. A very short trans-ACPC tetramer with insufficient helical propensity self-assembled into well-defined microtubes with rectangular cross-section on surface by the evaporation-induced self-assembly (EISA) process. Conformational instability and heterogeneity of trans-ACPC tetramer in solution state were identified by 2D NMR and circular dichroism analyses. Surprisingly, single crystal X-ray diffraction and PXRD analyses revealed that the molecular arrangements in crystal and in the tubular assembly were essentially identical. In case of trans-ACPC hexamer, unusual hollow parallelopiped-shaped self-assembled structures were obtained by EISA process. Distinct pseudopolymorphism in the assembled structure and chiral expression at the supramolecular level were observed. Self-assembly of the analogues of trans-ACPC hexamer revealed the effect of terminal groups on the three-dimensional supramolecular morphology. Formation mechanisms of tubular assemblies of trans-ACPC tetramer and hexamer were suggested based on diffusion-limited mass transport. This dissertation, which is about the novel self-assembly phenomena of unnatural $\beta$ -peptides, is ex-pected to contribute to the development of artificial functional complexes and diverse applications in biological and material science.