Reprogramming Chirality in Peptide Self-Assembly via Intramolecular Side Chain-Backbone Hydrogen Bonding

Area of Science:

• Biochemistry
• Supramolecular Chemistry
• Materials Science

Background:

• Protein structure is maintained by main chain-main chain and side chain-side chain interactions.
• The role of main chain-side chain interactions, particularly with uncharged polar side chains, is underexplored.
• Uncharged polar side chains can modulate conformation via hydrogen bonding (H-bonding) with the protein backbone.

Purpose of the Study:

• To investigate the role of main chain-side chain H-bonding in peptide conformation and self-assembly.
• To explore how uncharged polar side chains influence peptide conformational preferences.
• To demonstrate a strategy for engineering peptide nanofibrils with specific chirality.

Main Methods:

• Synthesis and analysis of 15 minimalistic amphiphilic peptides.
• Investigation of intrastrand H-bonding between C-terminal side chains and the main chain.
• Characterization of conformational preferences and β-sheet assembly modes.

Main Results:

• Intrastrand H-bonding involving C-terminal uncharged polar side chains dictates peptide conformational preferences.
• Serine and threonine side chains significantly alter single-strand conformations.
• This alteration reprograms interstrand H-bonding in β-sheet assembly, leading to distinct right-handed supramolecular chirality.

Conclusions:

• Polar side chain-backbone H-bonding is a key determinant of peptide chirality.
• This mechanism provides a rational design strategy for creating peptide nanofibrils with controlled, rare right-handed chirality.
• The findings advance the understanding of peptide self-assembly and biomaterial design.