Ambidextrous α,γ-Hybrid Peptide Foldamers

Area of Science:

• Supramolecular Chemistry
• Organic Chemistry
• Biochemistry

Background:

• Molecular chirality is fundamental in nature, with proteins and DNA exhibiting a right-handed helical bias.
• Understanding the factors that control helical conformations in peptides is crucial for biomimetic design.

Purpose of the Study:

• To investigate the helical conformations of α,γ-hybrid peptide foldamers.
• To explore the co-existence of left- and right-handed helices within a single molecule.
• To examine the helix-terminating properties of specific amino acid residues.

Main Methods:

• Synthesis of α,γ-hybrid peptides incorporating α-aminoisobutyric acid (Aib) and 4-amino-3,3-dimethylbutanoic acid (Adb).
• Analysis of molecular conformations using techniques such as X-ray crystallography and solution-state NMR.
• Computational modeling to understand folding behavior and stereochemical influences.

Main Results:

• Demonstrated the rare co-existence of left- and right-handed helical conformations in a single α,γ-hybrid peptide molecule.
• Identified a helix-terminating property associated with C-terminal Adb residues.
• Observed that dialkyl substitutions on γ-amino acids significantly influence peptide folding.

Conclusions:

• α,γ-hybrid peptide foldamers can display complex helical behaviors, including inversions in screw sense.
• The C-terminal Adb residues act as effective helix terminators, enabling the design of novel peptide structures.
• Stereochemical modifications of γ-amino acids provide a powerful tool for controlling peptide foldamer architecture.