Protein folding pathways
This blog post addresses another question that was neglected in our last Science chat:
Is there any pathway for natural folding? – Bruno Kestemont
This an excellent question, but unfortunately it does not have a simple answer. The folding pathway—sometimes discussed as "folding kinetics"—describes how an unfolded protein transitions to its native fold over the course of time. In general, folding pathways are poorly understood, but it is an area of active research (in fact, our very own David Baker started off studying the kinetics of protein folding in the '90s!).
Most of us working with Foldit or Rosetta do not think much about folding pathways (as one colleague put it, "Who cares?"). We lean heavily on the assumption that a chain of amino acids will naturally adopt its lowest-energy structure (see Anfinsen's dogma), and we don't worry too much about the path required to get there. In other words, we're more interested in how a protein system behaves at equilibrium; exactly how the system reaches equilibrium is another matter. Coincidentally, I am not an expert in folding kinetics, but I can touch on the main points.
Most people agree that strong, local interactions will form first (e.g. the short-range hydrogen bonds that stabilize α-helices and β-hairpins); and weak, nonlocal interactions will form more slowly (e.g. β-strand pairings between distant residues, interactions between pre-folded domains, etc.).
Many small proteins seem to fold via a concerted, two-state mechanism. You might imagine that such a protein is translated completely by the ribosome, and exists briefly as a random coil in solution before collapsing all-at-once into a stable fold. We observe such proteins in only two states: either completely unfolded or completely folded. This is the most likely scenario for the types of small proteins (<150 residues) that are encountered in Foldit puzzles.
Larger proteins seem to follow more complex, multi-state folding pathways. In some cases, we can actually observe multiple populations of a protein that exists in various, discrete stages of “foldedness.” Many of these proteins even fold co-translationally in the cell, so that the N-terminus of the protein might be completely folded before the ribosome finishes translating the C-terminus. In fact, there is evidence that certain genes have evolved “brake” regions in their mRNA, which actually slow down the ribosome at certain points during translation so that the N-terminus has a chance to fold before the C-terminus is translated.
If you want to know more (and we hope you do), I strongly recommend this review article by Dill et al. It is a clearly-written overview intended for readers outside of the field. And, like any good review, it includes many pages of references for more curious readers.