Enantiopurity-Dependent Peptide Coacervates and Asymmetric Organocatalysis

Membraneless compartmentalization via liquid-liquid phase separation (LLPS) has emerged as a powerful strategy to organize biochemical reactions. Recently, peptide-based coacervates demonstrated the potential to function as microreactors by enhancing reaction kinetics through increased local concentrations and altered microenvironments. Here, we introduce an O-methylated diphenylalanine-based tripeptide ^LLLPFF-OCH₃ containing an N-terminal proline, designed to undergo LLPS, and simultaneously function as an enantioselective organocatalyst. Comprehensive characterization via confocal microscopy, fluorescence recovery after photobleaching (FRAP), micro-Raman and attenuated total reflection infrared (ATR-IR) spectroscopy, diffusion-surface plasmon resonance (D-SPR), and molecular dynamics (MD) simulations revealed the formation of stable liquid droplets. In contrast, a racemic mixture of ^LLLPFF-OCH₃ and ^DDDPFF-OCH₃ failed to form liquid droplets and instead formed a solid precipitate, unveiling a critical role of enantiopurity in LLPS. Proof-of-concept catalytic studies proved enantioselective organocatalytic activity of the ^LLLPFF-OCH₃ liquid coacervates. Beyond catalysis these results may have broader implications in understanding prebiotic chemistry and neurodegeneration.