The protein folding problem constitutes a major challenge in molecular biophysics. As the drama unfolds and people feel increasingly powerless, most researchers working in the field rather tell the protein what to do than absorb the lesson from Nature. As a result, the emerging theories are often as relevant to protein folding as ornithology is to birds. In an earnest attempt to face the challenge, Ariel Fernandez found a semiempirical solution. This solution is rooted in the principles of physics and effectively addresses certain theoretical imperatives that -in our view- have not been properly dealt with before. These imperatives are:
I. The incorporation of realistic timescales for conformational exploration.
II. The identification of the physical basis of folding cooperativity.
III. The computation of the protein-water interfacial tension and its steering contribution to folding dynamics.
The first imperative was fulfilled with the discovery of "torsional dynamics modulo Ramachandran basins", a coarse-grained stochastic model of the backbone metadynamics implemented by Ariel Fernandez in 1999. The metadynamics is susceptible of being fleshed out into all-atom dynamics as needed to determine transitions between coarse states.
The second imperative was fulfilled with the discovery of three-body electrostatic-wrapping correlations by Ariel Fernandez and collaborators in 2001. These correlations account for the environmental dependence of the strength and stability of intramolecular electrostatic interactions.
The third imperative was fulfilled with Ariel Fernandez's first computation of the protein-water interfacial tension. This computation is based on an elastic model of the structural distortion of the water matrix, proposed in 2011-2013 and required a multiscale theory of water dielectrics. In accord with this model, the structural defects known as dehydrons are causative of interfacial tension and embody an exquisite interplay between biomolecular interactions and interfacial behavior.
After many fruitless attempts, we decided that the physical picture captured by Ariel Fernandez's folding trajectories may be best conveyed by resorting to metaphor:
"Protein folding is the struggle for the survival of intramolecular hydrogen bonds."