A short peptide synthon for liquid–liquid phase separation

Liquid-liquid phase separation of disordered proteins has emerged as a
ubiquitous route to membraneless compartments in living cells, and
similar coacervates may have played a role when the first cells formed.
However, existing coacervates are typically made of multiple
macromolecular components, and designing short peptide analogues capable
of self-coacervation has proven difficult. Here we present a short
peptide synthon for phase separation, made of only two dipeptide
stickers linked via a flexible, hydrophilic spacer. These small-molecule
compounds self-coacervate into micrometre-sized liquid droplets at
sub-millimolar concentrations, which retain up to 75 wt% water. The
design is general and we derive guidelines for the required sticker
hydrophobicity and spacer polarity. To illustrate their potential as
protocells, we create a disulfide-linked derivative that undergoes
reversible compartmentalization controlled by redox chemistry. The
resulting coacervates sequester and melt nucleic acids, and act as
microreactors that catalyse two different anabolic reactions yielding
molecules of increasing complexity. This provides a stepping stone for
new coacervate-based protocells made of single peptide species.