Local RNA Structure, Ion Hydration Shell, and the Energy Barrier for Water Exchange from the Ion Hydration Shell Determine the Mechanism of Ion Condensation on Specific RNA Sites

Abstract RNA folding and functioning require the binding of metal ions in specific cavities of the folded structure, especially in riboswitches that regulate metal ion concentrations. However, the fundamental principles governing the specific binding of metal ions to RNA are unclear. We probed the condensation mechanism of biologically relevant alkali (Na+ and K+), alkaline-earth (Mg2+ and Ca2+), and transition metals (Mn2+, Co2+, Ni2+, and Zn2+) on a part of the Ni2+ and Co2+ (NiCo)-sensing riboswitch using computer simulations. The selected structure has multiple secondary structural elements and a single site for ion binding. We show that three factors primarily determine ion binding to the RNA site: (1) the varying structural constraints from different RNA secondary structural elements; the mode of ion binding depends on the local structure of the RNA around the ion-binding pocket; (2) the arrangement of water molecules in the ion hydration shell; and (3) the energy barrier for the ion to lose a water molecule from its hydration shell and transition from an outer- to an inner-shell interaction. These results have implications for designing biocompatible sensors using riboswitches to probe the concentrations of intracellular metal ions.