Journal of colloid and interface scienceDec 9, 2025

How the order of amino acids controls phase behavior and function of short peptide droplets

mRNA Technology Weekly Brief ↗PubMed ↗DOI ↗

Updated Jan 7, 2026

Abstract

The phase separation behavior of short cysteine-terminated peptides is primarily determined by the ratio of arginine to aromatic residues.

LLPS in these peptide systems is influenced by the specific identity of aromatic residues, including phenylalanine, tyrosine, and tryptophan.
A linear correlation exists between the saturation concentrations and the hydrophobicity of the aromatic residues, suggesting that greater hydrophobicity enhances phase separation.
Incorporating an enzyme-inspired catalytic triad into peptide sequences imparts catalytic activity to the coacervates.
Redox-active disulfide spacers allow for reversible condensation and dissolution in response to glutathione, which may aid in intracellular delivery.
These findings provide a framework for designing peptide-based coacervates with potential applications in mRNA vaccines and the study of life's chemical origins.

Simplified

Membraneless compartments formed through liquid-liquid phase separation (LLPS) of intrinsically disordered proteins are essential for cellular organization and regulation. Similarly, short peptide-based coacervates assembled via LLPS may have served as primitive compartments during early biochemical evolution. However, the molecular grammar that governs the phase behavior of short peptides remains elusive. Here, we present a library of short cysteine-terminated peptides that act as "sticker" units to systematically investigate the phase separation behavior of their oxidized dimeric forms. Our findings reveal that LLPS in these simple peptide systems is primarily determined by the apparent ratio of arginine to aromatic residues (R) and by the specific identity of the aromatic residue (Phe, Tyr, Trp). The measured saturation concentrations (C) exhibit a linear correlation with the hydrophobicity of the aromatic residues, indicating that increased hydrophobicity enhances the driving force for phase separation. To demonstrate their functional versatility and relevance as protocell models, we incorporated an enzyme-inspired catalytic triad (Ser-His-Asp, SHD) into the peptide sequences, thereby imparting catalytic activity to the coacervates. Moreover, redox-active disulfide spacers enabled reversible condensation and dissolution in response to glutathione, facilitating intracellular delivery and glutathione-triggered release of cargos such as mRNA. Together, these findings establish a minimal yet predictive framework for the design of peptide-based coacervates and highlight their potential in intracellular delivery, mRNA vaccines, and studies on the chemical origins of life. arg/aro sat

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Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper

PubMed

How the order of amino acids controls phase behavior and function of short peptide droplets

Abstract

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