Solving the protein folding problem from physical principles is surely a daunting task and perhaps the main open challenge of the post-genomic era. It entails identifying the folding pathways that enable the protein to find its native structure and predict the latter solely from the amino acid sequence of the protein.
Progress in this area has been hampered by unproductive borderline-theological discussions on the modeling of the intramolecular energy and vagaries on the hydrophobic effect. Sorely missing from the discussion is the requirement of harmonious coexistence of the structure with the surrounding solvent. Thus, the native fold is expected to generate a minimal distortion of the water matrix relative to nonnative structures. To actually deal with the physics of structure-water coexistence, a bold step has now been taken by introducing an epistructural tension that can be computed and whose minimization is sought by the folding chain. Has the protein folding problem been finally solved? Time will tell and this may well be still in the eye of the beholder. So, check for yourself at
Ariel Fernandez (2013) The principle of minimal episteric distortion of the water matrix and its steering role in protein folding. Journal of Chemical Physics 139, 085101.
An exciting survey on the problem zooming in on this specific solution may be found in the blog “water in biology” (Chapter “water and protein folding”, October 7, 2013) by science writer Philip Ball.