Open Access

Thomas C. T. Michaels, L. Mahadevan, Christoph A. Weber

• Liquid condensates are membraneless organelles that form via phase separation in living cells. These condensates provide unique heterogeneous environments that have much potential in regulating a range of biochemical processes from gene expression to filamentous protein aggregation—a process linked to Alzheimer's and Parkinson's diseases. Here we theoretically study the physical interplay between protein aggregation, its inhibition, and liquid-liquid phase separation. Our key finding is that the action of protein aggregation inhibitors can be strongly enhanced by liquid condensates. The physical mechanism of this enhancement relies on the partitioning and colocalization of inhibitors with their targets inside the liquid condensate. Our theory uncovers how the physicochemical properties of condensates can be used to modulate inhibitor potency, and we provide experimentally testable conditions under which drug potency is maximal. Our findings suggest design principles for proteinLiquid condensates are membraneless organelles that form via phase separation in living cells. These condensates provide unique heterogeneous environments that have much potential in regulating a range of biochemical processes from gene expression to filamentous protein aggregation—a process linked to Alzheimer's and Parkinson's diseases. Here we theoretically study the physical interplay between protein aggregation, its inhibition, and liquid-liquid phase separation. Our key finding is that the action of protein aggregation inhibitors can be strongly enhanced by liquid condensates. The physical mechanism of this enhancement relies on the partitioning and colocalization of inhibitors with their targets inside the liquid condensate. Our theory uncovers how the physicochemical properties of condensates can be used to modulate inhibitor potency, and we provide experimentally testable conditions under which drug potency is maximal. Our findings suggest design principles for protein aggregation inhibitors with respect to their phase-separation properties.…