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.

Relevant Videos
Ariel Fernandez describes a first-principle solution to the protein folding problem
Missing science needed to solve the protein folding problem

Ariel Fernandez webpage


  1. I just found an account by the great science writer Philip Ball on the paper that Ariel Fernandez published in JCP (2013). I am transcribing the main portions of Ball’s account (full review in the blog “water in biology”):

    “He [Ariel Fernandez] presents a model of electrostatic interactions between the protein surface and water dipoles, which suggests a principle that Ariel calls minimal episteric distortion: the protein-water interface adopts a configuration that minimizes the energetic cost of disrupting dipole interactions of the hydrogen-bonded matrix. In other words, the native fold is the one that corresponds to this minimally perturbing topology: the protein structure is the one that is least at odds with the structure of the surrounding water. As Ariel has put it, “The paper shows that the full interfacial free energy can be computed/interpreted in two different but equivalent ways: a) as elastic energy arising from the perturbation of the hydrogen-bond matrix of water, or b) as electrostatic energy stored in the anomalous polarization of water (interactions between dipoles forced not tobehave in Debye manner and protein charges).” And crucially, if this interfacial free energy is omitted from the folding computations, an incorrect fold results because the structure is then “at odds with the solvent”.


  2. So, according to Ariel Fernandez there is an anomalous (non-Debye) water polarization never seen before due to the complexities of the protein-water interface? Sounds reasonable. Then there must be a torque on the protein electric field caused by these naughty dipoles, so the solvent is steering the folding process. OK?


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