Small molecule modified peptides are used to regulate their liquid-liquid phase separation characteristics

Abstract

Liquid-liquid phase separation (LLPS) is a phenomenon in which a uniform mixture spontaneously divides into two liquid phases with differing component concentrations. It is prevalent in soft matter, is observed in systems involving polymers, organic molecules, and proteins, and is influenced by environmental factors and component properties. Short peptides can also form droplets with LLPS phenomenon. It is generally believed that the formation of LLPS is restricted by the hydrophilicity and hydrophobicity of small molecules as well as their charge. The modulation of phase separation behaviors in short peptides offers a promising avenue for developing biomimetic materials and understanding subcellular organization. In this study, we report a simple yet effective strategy to tune the phase separation properties of a short peptide by conjugating its C-terminus with linear alcohols of varying chain lengths via esterification. Our results reveal that the length of the alkyl chain critically influences the phase separation propensity and the resulting material properties. No modification and short-chain modifications led to homogeneous solutions, whereas long chains promoted the formation of liquid-like condensates. This work establishes C-terminal esterification as a facile post-synthetic modification strategy to precisely control peptide phase behavior, providing new insights into the design of tunable biomolecular condensates and peptide-based materials.