How Droplets Can Accelerate Reactions─Coacervate Protocells as Catalytic Microcompartments

ConspectusCoacervates are droplets formed by liquid–liquid phase separation (LLPS) and are often used as model protocells–primitive cell-like compartments that could have aided the emergence of life. Their continued presence as membraneless organelles in modern cells gives further credit to their relevance. The local physicochemical environment inside coacervates is distinctly different from the surrounding dilute solution and offers an interesting microenvironment for prebiotic reactions. Coacervates can selectively take up reactants and enhance their effective concentration, stabilize products, destabilize reactants and lower transition states, and can therefore play a similar role as micellar catalysts in providing rate enhancement and selectivity in reaction outcome. Rate enhancement and selectivity must have been essential for the origins of life by enabling chemical reactions to occur at appreciable rates and overcoming competition from hydrolysis.In this Accounts, we dissect the mechanisms by which coacervate protocells can accelerate reactions and provide selectivity. These mechanisms can similarly be exploited by membraneless organelles to control cellular processes. First, coacervates can affect the local concentration of reactants and accelerate reactions by copartitioning of reactants or exclusion of a product or inhibitor. Second, the local environment inside the coacervate can change the energy landscape for reactions taking place inside the droplets. The coacervate is more apolar than the surrounding solution and often rich in charged moieties, which can affect the stability of reactants, transition states and products. The crowded nature of the droplets can favor complexation of large molecules such as ribozymes. Their locally different proton and water activity can facilitate reactions involving a (de)protonation step, condensation reactions and reactions that are sensitive to hydrolysis. Not only the coacervate core, but also the surface can accelerate reactions and provides an interesting site for chemical reactions with gradients in pH, water activity and charge. The coacervate is often rich in catalytic amino acids and can localize catalysts like divalent metal ions, leading to further rate enhancement inside the droplets. Lastly, these coacervate properties can favor certain reaction pathways, and thereby give selectivity over the reaction outcome.These mechanisms are further illustrated with a case study on ribozyme reactions inside coacervates, for which there is a fine balance between concentration and reactivity that can be tuned by the coacervate composition. Furthermore, coacervates can both catalyze ribozyme reactions and provide product selectivity, demonstrating that coacervates could have functioned as enzyme-like catalytic microcompartments at the origins of life.