Emerging themes in RNA folding

RNAs, like proteins, readily form specific structures adapted for ligand binding and catalysis. Since they are composed of completely different chemical building blocks, however, RNAs and proteins necessarily use distinct strategies to assemble complex architectures. While burial of hydrophobic residues drives protein folding, the hydrophobic effect in RNA contributes primarily to the formation of secondary structure. To form tertiary structure, RNA must overcome electrostatic repulsions from the phosphate backbone. How do negatively charged double helices pack together to produce catalytic centers and ligand binding surfaces? Here, we review our understanding of the principles that underlie RNA folding based on the structural information currently available.