Solving the protein folding problem…

The protein folding problem was, to paraphrase Churchill, 'A riddle wrapped in a mystery inside an enigma'. The riddle, in this context, was the folding code; what interactions at the amino acid level are driving the folding process? The mystery was the kinetic question (Levinthal's paradox); how does the folding process occur so quickly (typically in timescales ranging from μS to mS)? Finally, the enigma represents the computational problem of developing approaches to predict the final folded sate of a protein given only its amino acid sequence. Herein, I trace the path to solving this riddle wrapped in a mystery inside an enigma.