The RNA Folding Problem

Because the chemical and biological properties of many RNAs are determined by their conformations, an RNA equivalent exists to the protein folding problem. The RNA folding problem has both a practical side and an academic side. If the practical problem were solved, it would be possible to predict the conformations of RNAs of known sequence. The academic problem has to do with determining what happens when denatured RNAs fold in vitro, and nascent RNA chains fold in vivo. The focus of this essay is structure prediction, but it does include some commentary on what has been learned about RNA folding pathways. Structure prediction is a matter of some urgency today because RNAs are being discovered much faster than their three-dimensional structures are being solved. Furthermore, the techniques available for determining structures experimentally, X-ray crystallography and NMR, are so timeconsuming, applied to RNAs by communities so small, and so uncertain of success when applied to specific RNAs that, absent some technological and/or sociological revolution, the mismatch between supply and demand is certain to persist indefinitely. In principle, biochemists ought to be able to do without the services of crystallographers and NMR spectroscopists. Most (all?) denatured RNAs renature spontaneously in vitro, which means that the structures of RNAs are determined by their sequences. Furthermore, the physical interactions that drive RNA folding are largely understood (see Chapter 10). Why can’t the structures of RNAs of known sequence be predicted, and failing that, why can’t procedures be developed that determine conformations by combining theory with nonphysical data?