ABSTRACT Metastable states are utilized by biology to power the construction of large and motile macromolecules and also to realize out‐of‐equilibrium phase separation. Energy transduction from orthogonal and unrelated exergonic reactions drives the contra‐thermodynamic transformation, which acts as the catalyst for the exergonic reaction. Herein, we show that thermodynamically stable building blocks can undergo phase separation when the process is coupled with an exergonic degradation of their thermodynamically activated precursor. The thermodynamically stable products alone are incapable of accessing the droplets. The chemical transformation is critical to achieve pathway‐controlled phase separation, which catalyzes the chemical transformation. The activated precursor undergoes a β‐elimination reaction to produce an aromatic substrate along with trimethylammonium cations, which provide temporal stabilization to the phase‐separated droplets. Droplet formation is not observed with precursors incapable of undergoing the β‐elimination reaction. The generated droplets can imbibe diverse guest molecules, and their transition from droplets to proto‐tissue‐like structures is observed in the presence of porphyrin. Importantly, the kinetically accessed metastable liquid droplets are shown to augment the catalytic potential of hemin, cofactor of natural peroxidase, and accelerate the hydrolase‐peroxidase cascade reaction.
Pal et al. (Tue,) studied this question.