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. The protein folding problem consists of three parts: (a) the folding code considers the intermolecular forces dictating the amino acid interactions which cause the polypeptide to fold; (b) the kinetic question centres on the speed of the folding process, while (c) the computational problem is focused on how the final folded protein shape can be predicted solely from its amino acid sequence.