How do proteins fold and why do they fold in that way?
These questions have engaged the experimentalists and
theoreticians with gathering intensity since about 1960,
when Chris Anfinsen first showed that proteins are able to fold to their native structure
all by themselves, without outside help.
Here's a slide of Anfinsen's classical experiment.
He unfolded the protein ribonuclease A in
chemical denaturating, that is with concentrated urea.
Carefully reduced all four of
the covalent disulfide bonds that stabilize the native structure.
Actually, that was the hard part.
Then he put the protein back into native conditions: no denaturing,
normally oxygenated buffer and watched
ribonuclease spontaneously reform its normal disulfides,
refold to end and recover its native enzymatic activity, pretty exciting.
In this case, however,
the folding reaction went on a timescale of hours,
limited not by the difficulty of spontaneous refolding,
but by the slow rate for reforming the native disulfides.
Later on we'll see that proteins fold an awful lot faster than that.
On this basis, Anfinsen framed his famous Thermodynamic hypothesis, that protein folding,
just like any other spontaneous chemical process,
simply proceeds energetically downhill to its lowest free energy form, the native state.
Soon after, Cyrus Levinthal suggested the opposite view,