Tertiary structures, self-sorting behavior, and formation of an eight helix bundle of helical aromatic δ-amino acid abiotic foldamers in organic solvents

Menke, Friedericke (2023): Tertiary structures, self-sorting behavior, and formation of an eight helix bundle of helical aromatic δ-amino acid abiotic foldamers in organic solvents. Dissertation, LMU München: Fakultät für Chemie und Pharmazie

Abstract

The structure-function relationship of biopolymers inspired the field of foldamers, synthetic oligomers that adopt well-defined three-dimensional structures. In the pursuit of accessing unnatural shapes and functions, different from peptides, research led to the field of abiotic foldamers. In this context, side chain positioning and thereby functional design have been greatly simplified by using oligo-quinolinecarboxamides, known to adopt predictable helical structures. Thus, the formation and shape of a tertiary structure has been successfully predicted by computational modelling and verified by X-ray crystallography. The structure consisted of a helix-turn-helix-motif stabilized by inter-helical hydrogen bonds. In this work the correlation between the conformational preference inherent to each helix and the stability of the tertiary structure was investigated. Therefore, helix-turn-helix sequences were synthesized in which some hydrogen bonds have been removed. Unexpectedly, no strong destabilization of the tertiary fold has been observed. Examination of a new crystal structure revealed that helices adopt their natural curvature when some hydrogen bonds are missing. Otherwise, these hydrogen bonds enforce a spring torsion on the helices, thus causing a conformational frustration as it exists in proteins. This observation also helped increase the understanding of aggregational patterns formed in self-assemblies in which helices were no longer bound to one another by a turn unit. In this case, different kinds of intermolecular hydrogen bonding interfaces in solution have been observed involving two linear arrays of hydrogen bond donors and acceptors at the surface of the helices. In the aim to simplify aggregational behavior, sequences containing only one linear array of hydrogen bond donors and acceptors at their surface have been synthesized. Sequences were synthesized on solid phase and their aggregational behavior examined via solution 1H NMR spectroscopic studies and solid state crystallographic structures. These showed the formation of stable hydrogen bond-mediated dimeric helix bundles that could be either heterochiral (with a P and an M helix) or homochiral (with two P or two M helices). Thus, these foldamers displayed either a social or narcissistic chiral self-sorting behavior. This behavior could be influenced by using different chlorinated solvents, thereby causing quantitative formation of the hetero- or homochiral dimers. Another way to influence aggregation behavior is to forbid PM species by imposing absolute handedness to the helices. Summing up, in this kind of self-assembly a new hydrogen bonding interface imposing some sort of parallelism on the helices has been discovered. However, to access more diverse complex structures, the formation of non-parallel motifs such as tilted dimers, should become more predictable. Therefore, a flexible linker to stabilize a tilted dimer was designed using a crystal structure of such a dimer as starting point. The design was validated. However, the flexible linker also allowed for the discovery of an abiotic, tetrameric, eight-helix bundle. This large (>12 kDa) discrete aggregate is stabilized via inter- and intra-molecular hydrogen bonds, featuring several hydrogen bonding interfaces, including some that had not yet been reported. The discovery of this complex structure provides insights into future designs and enables the prediction of more diverse and sophisticated self-organizations.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Keywords: abiotic foldamers in organic solvents, tertiary structures, self-sorting behavior, formation of an eight helix bundle
• Themengebiete: 500 Naturwissenschaften und Mathematik ; 500 Naturwissenschaften und Mathematik > 540 Chemie
• Fakultäten: Fakultät für Chemie und Pharmazie
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 7. März 2023
• 1. Bericht­erstatter:in: Huc, Ivan