Binary peptide coacervates as an active model for biomolecular condensates

Abstract Biomolecular condensates formed by proteins and nucleic acids are critical for cellular processes. Macromolecule-based coacervate droplets formed by liquid-liquid phase separation serve as synthetic analogues, but are limited by complex compositions and high molecular weights. Recently, short peptides have emerged as an alternative component of coacervates, but tend to form metastable microdroplets that evolve into rigid nanostructures. Here we present programmable coacervates using binary mixtures of diphenylalanine-based short peptides. We show that the presence of different short peptides stabilizes the coacervate phase and prevents the formation of rigid structures, allowing peptide coacervates to be used as stable adaptive compartments. This approach allows fine control of droplet formation and dynamic morphological changes in response to physiological triggers. As compartments, short peptide coacervates sequester hydrophobic molecules and enhance bio-orthogonal catalysis. In addition, the incorporation of coacervates into model synthetic cells enables the design of Boolean logic gates. Our findings highlight the potential of short peptide coacervates for creating adaptive biomimetic systems and provide insight into the principles of phase separation in biomolecular condensates.