Here I am concerned with a solution to the protein folding problem that relies solely on the first principles of physics. These principles govern the solvent-mediated exploration of conformation space by a self-interacting protein chain. Strikingly, such a solution remains nearly as elusive as the first day the problem was posed. This surely has to do in part with the wanton difficulty of the problem but a lot more with the sociology and psychology of those involved in the business. Like never before, the noise in the field of molecular biophysics proves to be far louder than the signal. Sometimes it feels like whoever shouts the most and lobbies more ardently gets the upper hand. It is easy to fool oneself, and perhaps each of us is the easiest person to fool.

An ab-initio solution remains forbiddingly out of reach, mostly because the force fields cannot meaningfully account for the interfacial phenomena at stake [Ariel Fernandez: How do proteins dry in water? Journal of Physics Condensed Matter, News Item, May 1, 2014]. The latter require a multiscale theory of water, which is still not in the cards, or so it seems. On the other hand, semiempirical approaches have proven particularly deceitful, as they build in the answer into the search process or into disguised knowledge-based force fields. On top of this, many absurdities keep hovering over the discussion, clouding our precarious understanding, with few discerning minds able or willing to shake them off once and for all. In this bag we should place the religious belief that the native fold must realize the free energy minimum in conformation space or that the problem is difficult because of the vastness of conformation space, as if the search for the native fold were a random vagary. If the former is a baseless statement, the latter is perhaps even more absurd, something akin to stating that I cannot go home tomorrow because of the vastness of places where I could in principle go instead. Just try to fathom the perplexity of your wife, husband or significant other if faced with that utterance.

The type of solution we seek as physicists requires that we deal squarely with the protein-water interface in physical terms [Ariel Fernandez, Journal of Physics Condensed Matter 26, 202101 (2014)]. Soluble proteins cannot expose their polar backbone to water in their native folds since hydration of the backbone polar groups compromises the structural integrity of the protein. These considerations prompted me to examine subnanoscale structural defects known as dehydrons [Ariel Fernandez: “Transformative Concepts for Drug Design: Target Wrapping”, Springer-Verlag, Berlin, 2010], defined precisely as water-exposed backbone hydrogen bonds, and determine the electrostatic properties of the protein-water interface at dehydron locations. This proves particularly difficult because the classical electrostatic picture, where water orients itself along the electrostatic field of the biomolecule, breaks down for nanoscale confinement around dehydrons, causing interfacial tension. This result represents a significant departure from standard thinking that still adheres tenaciously to a Debye picture of water polarization. The interfacial tension actually steers protein folding, and this dominant role becomes apparent in the semiempirical solution that emerges from the folding trajectories that I have generated. Ultimately, my solution invites the formulation of an action principle that singles out the expeditious folding trajectories as those that entail the minimal work required to remove the episteric water molecules that cause interfacial tension.

After a long agony in search for a meaningful approach perhaps the most revealing picture that comes to my mind may be captured in a single phrase: “folding is the struggle of the protein chain to get dry in water”.

Ariel Fernandez

Ariel Fernandez’s solution to the protein folding problem (YouTube)

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