Selective Ion Binding and Uptake Shape the Microenvironment of Biomolecular Condensates

Biomolecular condensates modulate various ion-dependent cellular processes and can regulate subcellular ion distributions by selective uptake of ions. To understand these processes, it is essential to uncover the molecular grammar governing condensate-ion interactions. Here, we use nuclear magnetic resonance (NMR) spectroscopy of ions and model condensate components to quantify and spatially resolve selective ion binding to condensates and show that these interactions follow the "law of matching water affinities", resulting in strong binding between proteins and chaotropic anions and between nucleic acids and kosmotropic cations. Ion uptake into condensates directly follows binding affinities, resulting in selective uptake of strong-binding ions but exclusion of weak-binding ions. Ion binding further shapes the condensate microenvironment by altering the composition, viscosity, and interface potential. Such changes can have profound effects on biochemical processes taking place inside condensates, as we show for RNA duplex formation. Our findings provide a new perspective on the role of condensate-ion interactions in cellular bio- and electrochemistry and may aid the design of condensate-targeting therapeutics.