""...which is incredibly complex and requires many computations to calculate all possible angles for each peptide to fold, while taking into account electrostatic interactions and solvent effects.

As an example of the effect solvents have, hydrophobic pockets in proteins are often tucked inside the protein— far away from any water.

A semi-practical example to show what I mean in real-life terms is that a protein, with a three-dimensional structure resulting from the folding of its individual amino acid constituents, once denatured (boiled to at least 95C), can then be approximated as being permanently useless— unable to serve its previous biochemical function.

This is the theory behind boiling water as an anti-microbial method— you’re able to denature any viral, or other, proteins which may be in solution, and the probability of them spontaneously refolding into their biochemically active state can be approximated to zero.

There are too many possible ways for the protein to fold, so spontaneous refolding is unlikely (in the statistical, computer-science sense) to reoccur in vitro.""

https://www.quora.com/What-are-the-mathematics-of-protein-folding