Nature-Inspired C-terminus Modification of Oligo-prolines to Stabilize PPII Helix

Oligomers of proline (oligo-Pro) are valuable models for studying the structural and thermodynamic properties of the all-trans polyproline II (PPII) helix. These peptides, in their rigid PPII form, serve as spectroscopic and molecular rulers. However, proline cis/trans isomerization can lead to the undesired all-cis PPI conformation in nonpolar solvents. In this study, we investigated mechanisms to stabilize the PPII structure by analyzing PPII regions in the Protein Data Bank (PDB) and observed a high prevalence of α-helices and β-turns at the C-termini of PPII helices. These motifs likely contribute to PPII stabilization through CO∙∙∙HN hydrogen bonding with the C-terminal carbonyl. To probe this, we synthesized oligo-Pro peptides of varying lengths, each capped with C-terminal β-turns. These peptides exhibited enhanced PPII stability, even in solvents that typically favor PPI. Our findings suggest that C-terminal hydrogen bonding promotes CO∙∙∙CO n → π* interactions within the peptide chain, playing a key role in stabilizing the PPII helix. These insights offer new strategies for designing stable PPII peptides and understanding the underlying mechanisms of PPII stabilization.