Metal-ion induced coacervation of a short peptide under acidic conditions.

Abstract

Coacervates formed from short peptides have recently emerged as versatile soft materials with applications in catalysis and biomimetic systems. However, liquid-liquid phase separation of short peptides typically requires charge neutralization, limiting coacervate formation under acidic conditions. Here, we show that Zn²⁺ induces coacervation of a diphenylalanine methyl ester in acidic media. This results in peptide-rich, low-polarity droplets that persist for several hours before undergoing a liquid-to-solid transition into fibrous assemblies. Spectroscopic and compositional analyses reveal that Zn²⁺ is enriched in the dense phase and interacts with peptide carbonyl groups while remaining partially hydrated. Computational calculations support this mechanism, showing that direct Zn²⁺ to carbonyl coordination is energetically unfavorable in aqueous solution, consistent with the small carbonyl shifts observed by FTIR. Despite these weak interactions, Zn²⁺ promotes coacervation under high ionic strength conditions. The addition of secondary metal ions further suppresses solidification, stabilizing coacervates for up to seven days without fiber formation. Co-metals also modulate droplet properties such as polarity and viscosity, enabling fine control over the coacervate phase. Together, these findings demonstrate that metal-peptide interactions can regulate phase behavior in minimal peptide systems at low pH and provide a strategy for designing metal-responsive coacervates.