Understanding RNA-Metal Ion Interactions: RNA Folding Pathways and Ion Selectivity

Abstract

Ribonucleic acid (RNA) plays diverse and critical roles in cellular function. For most biological functions, RNA must fold into specific three-dimensional structures, and physiologically abundant monovalent (Na+ and K+) and divalent (Mg2+) metal ions are required to neutralize the negatively charged phosphate backbone and facilitate RNA folding. The discovery of ion-sensing riboswitches in bacteria revealed that RNA structures can specifically bind transition metal ions and even anions such as F-, whose concentrations are multiple orders lower than that of Mg2+. The goal of my thesis is to understand the basic principles in RNA folding that lead to the specific binding of metal ions. To address this problem, I used riboswitches and introns as model RNA systems and studied their folding using computer simulations. I studied how these RNA systems fold in the presence of Mg2+ ions and at what stage in the folding process they distinguish between different metal ions and bind only to specific metal ions with high selectivity, even though there is a significant variation in the concentrations of different metal ions. I discuss the importance of the RNA folding intermediates, the inner and outer shell binding modes of solvated metal ions, and the local structure of the binding pocket in the selective binding of metal ions by RNA. These results have implications for the design of RNA-based metal ion sensors and antibiotic discovery, as riboswitches are targets for discovering new antibacterial molecules.