Georgia Institute of Technology College of Sciences

A 1986 article with this title, written by M. Zuker and published by the AMS, outlined several major challenges in the area. Stating the folding problem is simple; given an RNA sequence, predict the set of (canonical, nested) base pairs found in the native structure. Yet, despite significant advances over the past 25 years, it remains largely unsolved. A fundamental problem identified by Zuker was, and still is, the "ill-conditioning" of discrete optimization solution approaches. We revisit some of the questions this raises, and present recent advances in considering multiple (sub)optimal structures, in incorporating auxiliary experimental data into the optimization, and in understanding alternative models of RNA folding.