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

Abstract

While main chain-main chain and side chain-side chain interactions are known to maintain protein architectures, the role of main chain-side chain interactions remains largely unexplored. Among various amino acid side chains, uncharged polar ones may uniquely modulate molecular conformations through directional hydrogen bonding (H-bonding) with the main chain. Using 15 minimalistic amphiphilic peptides, we demonstrate that intrastrand H-bonding between C-terminal uncharged polar side chains and the main chain dictates conformational preferences. Specifically, serine and threonine side chains significantly alter single-strand conformations, thereby reprogramming interstrand H-bonding modes in β-sheet assembly and generating distinct right-handed supramolecular chirality. This study elucidates how polar side chain-backbone H-bonding controls chirality and provides a rational design strategy for engineering peptide nanofibrils with rare right-handed chirality.