Uncovering Rules Governing Small Molecule Partitioning into Condensates through Simulation

Understanding the rules governing the interactions between small molecules and biomolecular condensates is crucial for engineering effective therapeutics against condensate-related diseases. Previous studies have demonstrated that certain drugs selectively partition and concentrate within condensates, occasionally leading to their dissolution. In this work, we focus on physicochemical principles that govern the interactions between small molecules and condensates. We conducted all-atom explicit solvent molecular dynamics simulations of model condensates and small molecules. As model systems, we studied the interaction between phase-separating aromatic-rich peptides and small molecules with a variety of chemical structures. Notably, we have observed divergent partitioning tendencies among various small molecules. To reveal principles governing the partitioning of small molecules, we compute the potential of mean force between molecular components and inter-residue contact maps, as well as characterize the chemical makeup of individual drugs. Our data reveals that certain small molecules exploit high-affinity binding sites inside condensates, leading to their increased partitioning. Consequently, our study helps shed light on the rules that govern interactions between proteins in condensates and small organic molecules, which can be exploited for therapeutic design against condensate-associated diseases.