A Single Stereodynamic Center Modulates the Rate of Self‐Assembly in a Biomolecular System

Chirality is a property of asymmetry important to both physical and abstract systems. Understanding how molecular systems respond to perturbations in their chiral building blocks can provide insight into diverse areas such as biomolecular self‐assembly, protein folding, drug design, materials, and catalysis. Despite the fundamental importance of stereochemical preorganization in nature and designed materials, the ramifications of replacing chiral centers with stereodynamic atomic mimics in the context of biomolecular systems is unknown. Herein, we demonstrate that replacement of a single amino acid stereocenter with a stereodynamic nitrogen atom has profound consequences on the self‐assembly of a biomolecular system. Our results provide insight into how the fundamental biopolymers of life would behave if their chiral centers were not configurationally stable, highlighting the vital importance of stereochemistry as a pre‐organizing element in biomolecular folding and assembly events.     

A pH Switch for β‐Sheet Protein Folding

Protein design advancements have led to biotechnological strategies based on more stable and more specific structures. Herein we present a 6‐residue sequence (HPATGK) that acts as a stable structure‐nucleating turn at physiological and higher pH but is notably unfavorable for chain direction reversal at low pH. When placed into the turn of a β‐sheet, this leads to a pH switch of folding. Using a standard 3‐stranded β‐sheet model, the WW domain, it was found that the pH switch sequence insertion caused minimal change at pH 8 but a ca. 50 °C drop in the melting temperature (T_m) was observed at pH 2.5: ΔΔG_F ≥11.3 kJ mol⁻¹. Using the strategies demonstrated in this article, the redesign of β‐sheets to contain a global, or local, pH‐dependent conformational switch should be possible.