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Folding properties, handedness control and aggregation behavior of helical aromatic δ-amino acid foldamers in water
Folding properties, handedness control and aggregation behavior of helical aromatic δ-amino acid foldamers in water
Foldamers are an emerging class of molecules inspired by natural biopolymers, that also have the ability to fold into well-defined three-dimensional structures. As shape complementarity dictates many biological processes such as enzyme catalysis, signal transduction, and pathogen recognition, foldamers hold the potential to mimic and even extend the functions observed in proteins and nucleic acids. Over the decades, backbone types have been continually extended from β-peptides, which are still closely related to α-amino acids, to more abiotic oligomers. Aromatic oligoamides and aromatic δ-amino acids, in particular, offer easy synthetic access, amenability to solid phase synthetic methods and high folding propensity leading to helical structures that are very stable in most solvent environments. Thus, side chain positioning and geometry are well predictable, which offers a basis for functional designs. But tertiary and quaternary folds will ultimately be needed to unlock the true scope of these foldamers. This work describes a new family of aromatic δ-amino acid monomers based on 2-(2-aminophe-noxy)acetic acid (B). It was demonstrated that these more flexible units can be combined with the previously known aromatic δ-amino acid building blocks without significantly altering their canon-ical helical fold. The subtle differences in curvature of these units allow a fine-tuning of side chain positioning and stability of a given oligomer by adjusting its monomer composition and sequence order. Furthermore, a chiral B-unit was developed, which—when incorporated in the middle of aromatic helix sequences—proved to be able to bias handedness to over 99% towards one helicity. The monomer also induced handedness when positioned at the second or penultimate position of a sequence, albeit with weaker bias when close to the N-terminus. Thus, this unit enables designs that rely on both handedness control and free N- and C-termini for binding and/or further functionalization. Finally, the work describes the discovery of a binding interface between C-terminal aromatic helix cross sections leading to homochiral dimers in aqueous solution. Although they are based on aromatic stacking, the dimers are discrete, and their binding strength can be controlled by the nature of the side chains that are positioned close to the interface and the pH environment. By utilizing a primary amide terminus on one binding partner, exclusive heterodimer formation was achieved in the right concentration window. This binding interface can be useful in the future design of larger self-assembled structures. Conclusively, these findings represent important tools for the development of more sophisticated foldamer designs in aqueous media. Additionally, preliminary results of the formation of a side-to-side helix-aggregate (which has been a guiding goal throughout the research for this thesis) are presented. Strategies for bundle formation that have been utilized and challenges that still remain are discussed and should serve as a starting point for future designs.
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Bindl, Daniel
2022
English
Universitätsbibliothek der Ludwig-Maximilians-Universität München
Bindl, Daniel (2022): Folding properties, handedness control and aggregation behavior of helical aromatic δ-amino acid foldamers in water. Dissertation, LMU München: Faculty of Chemistry and Pharmacy
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Abstract

Foldamers are an emerging class of molecules inspired by natural biopolymers, that also have the ability to fold into well-defined three-dimensional structures. As shape complementarity dictates many biological processes such as enzyme catalysis, signal transduction, and pathogen recognition, foldamers hold the potential to mimic and even extend the functions observed in proteins and nucleic acids. Over the decades, backbone types have been continually extended from β-peptides, which are still closely related to α-amino acids, to more abiotic oligomers. Aromatic oligoamides and aromatic δ-amino acids, in particular, offer easy synthetic access, amenability to solid phase synthetic methods and high folding propensity leading to helical structures that are very stable in most solvent environments. Thus, side chain positioning and geometry are well predictable, which offers a basis for functional designs. But tertiary and quaternary folds will ultimately be needed to unlock the true scope of these foldamers. This work describes a new family of aromatic δ-amino acid monomers based on 2-(2-aminophe-noxy)acetic acid (B). It was demonstrated that these more flexible units can be combined with the previously known aromatic δ-amino acid building blocks without significantly altering their canon-ical helical fold. The subtle differences in curvature of these units allow a fine-tuning of side chain positioning and stability of a given oligomer by adjusting its monomer composition and sequence order. Furthermore, a chiral B-unit was developed, which—when incorporated in the middle of aromatic helix sequences—proved to be able to bias handedness to over 99% towards one helicity. The monomer also induced handedness when positioned at the second or penultimate position of a sequence, albeit with weaker bias when close to the N-terminus. Thus, this unit enables designs that rely on both handedness control and free N- and C-termini for binding and/or further functionalization. Finally, the work describes the discovery of a binding interface between C-terminal aromatic helix cross sections leading to homochiral dimers in aqueous solution. Although they are based on aromatic stacking, the dimers are discrete, and their binding strength can be controlled by the nature of the side chains that are positioned close to the interface and the pH environment. By utilizing a primary amide terminus on one binding partner, exclusive heterodimer formation was achieved in the right concentration window. This binding interface can be useful in the future design of larger self-assembled structures. Conclusively, these findings represent important tools for the development of more sophisticated foldamer designs in aqueous media. Additionally, preliminary results of the formation of a side-to-side helix-aggregate (which has been a guiding goal throughout the research for this thesis) are presented. Strategies for bundle formation that have been utilized and challenges that still remain are discussed and should serve as a starting point for future designs.