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Efficient encapsulation of proteins with random copolymers

Significance Inside cells of living organisms, aggregates rich in disordered proteins organize the local environment to promote cellular functions. These membraneless organelles are able to concentrate enzymes and biomolecules to regulate interactions via the multiple conformations and compositions of disordered proteins. The interior of these organelles seems to behave akin to organic solvents. This opens the possibility of assembling synthetic organelles using random copolymers that mimic disordered proteins to disperse and stabilize enzymatic proteins in different environments, including organic solvents. Here, we demonstrate that random copolymers with solvophobic and solvophilic groups can encapsulate numerous proteins, including Candida antarctica lipase B, subtilisin, cutinase, and pseudolysin, in basically any solvent. These aggregates are promising constituents of synthetic membraneless organelles. Membraneless organelles are aggregates of disordered proteins that form spontaneously to promote specific cellular functions in vivo. The possibility of synthesizing membraneless organelles out of cells will therefore enable fabrication of protein-based materials with functions inherent to biological matter. Since random copolymers contain various compositions and sequences of solvophobic and solvophilic groups, they are expected to function in nonbiological media similarly to a set of disordered proteins in membraneless organelles. Interestingly, the internal environment of these organelles has been noted to behave more like an organic solvent than like water. Therefore, an adsorbed layer of random copolymers that mimics the function of disordered proteins could, in principle, protect and enhance the proteins’ enzymatic activity even in organic solvents, which are ideal when the products and/or the reactants have limited solubility in aqueous media. Here, we demonstrate via multiscale simulations that random copolymers efficiently incorporate proteins into different solvents with the potential to optimize their enzymatic activity. We investigate the key factors that govern the ability of random copolymers to encapsulate proteins, including the adsorption energy, copolymer average composition, and solvent selectivity. The adsorbed polymer chains have remarkably similar sequences, indicating that the proteins are able to select certain sequences that best reduce their exposure to the solvent. We also find that the protein surface coverage decreases when the fluctuation in the average distance between the protein adsorption sites increases. The results herein set the stage for computational design of random copolymers for stabilizing and delivering proteins across multiple media.