Homogeneous and Robust Polyproline Type I Helices from Peptoids with Nonaromatic α-Chiral Side Chains

Area of Science:

• Peptide chemistry
• Supramolecular chemistry
• Materials science

Background:

• Peptoids, N-substituted glycine oligomers, are promising peptide mimics.
• Controlling backbone amide conformation is key for folded peptoid structures like polyproline type I (PPI) helices.
• Aromatic side chains previously showed success in promoting cis-amide conformations.

Purpose of the Study:

• To investigate the potential of sterically hindered α-chiral aliphatic side chains in forming stable peptoid helices.
• To synthesize and analyze peptoid homo-oligomers and mixed oligomers with these novel side chains.
• To achieve conformationally homogeneous helical peptoids using only aliphatic side chains.

Main Methods:

• Synthesis of (S)-N-(1-tert-butylethyl)glycine (Ns1tbe) peptoid homo-oligomers.
• X-ray crystallography to determine solid-state structure.
• Circular dichroism (CD) spectroscopy for conformational analysis.
• Synthesis and analysis of mixed peptoid oligomers containing Ns1tbe and N-tert-butylglycine (NtBu) monomers.

Main Results:

• The X-ray crystal structure of an Ns1tbe pentamer confirmed an all-cis PPI helix.
• CD curves of Ns1tbe oligomers matched those of PPI peptide helices.
• This is the first reported CD data for conformationally homogeneous helical peptoids with only α-chiral aliphatic side chains.
• A mixed oligomer, Ac-(tBu)2-(s1tbe)4-(tBu)2-COOtBu, exhibited a regular PPI helix in the solid state, despite containing only 50% chiral side chains.

Conclusions:

• Sterically hindered α-chiral aliphatic side chains can effectively promote the formation of all-cis PPI helices in peptoids.
• These findings expand the toolkit for designing conformationally controlled peptoid structures.
• The results open new avenues for peptoid applications in medicinal chemistry and biomaterials.