Every new folder, at some point, develops the urge to stretch out a new puzzle to be a long straight chain and then shake and wiggle it down into a final solution in the hopes that with only it's own internal characteristics the protein will pull itself into it's correct final state. After all, intuition tells us, putting aside divine intervention for the moment, that all of the important forces at work here are known. Of course, it never works out that way.
I've tried this more times than I'd care to admit. I've even tried stretching the amino acid chain out to a straight line; then freezing it all; then starting with #1 unfreezing while wiggling, shaking and rebuilding in hopes of recreating what it might be like to have a protein begin folding, even as it is being built, to no avail.
I can think of several reasons why not. First, I'm not so sure that all of the important forces have been accounted for. Yes, the chemistry of the amino acids are well understood; the geometry, too. But what about the surrounding environment. The water environment is all around. Since water is the third smallest molecule it must also exist between folds, as well. Moreover, the area of the cell outside the nucleus in which this is taking place is 15-20% composed of protein and protein fragments. Is any of this accounted for? I saw a very interesting YouTube animation that depicted this water environment in and around the protein molecule coming out of Croatia. I wished they had posted more.
Second, there are chaperones and chaperonin structures at work which are not well understood. I have found little information about these and would appreciate any further information you might know about out there. ONe video refers to the structure as a 'machine'. Another video called it a 'cage'. From the little information I have read, these play an important part in folding process. Fold.it might offer, as a tool much like bands, to allow folders to add a structure surrounding the protein in space which may serve to influence the folding by its 'gravity' and distance. Chaperones might also be added as a tool which simply act as a 'damper' on the amino acid chain to be added and then removed while the folding takes place.
Third, and this is more of a question than a comment, are the computations that are being made sequential? If so, can they accurately show the behavior we are looking for? In reality, each of the atoms are responding to all of the forces at work on it simultaneously. If the calculations in the Fold.it environment are done one at a time, by the time the 100th calculation for the 100th atom is made, the previous 99 atoms and their resulting positions have already shifted. Is it possible to do all of the calculations and then make the resulting shifts? This becomes a calculus problem trying to determine the resulting shift from anticipated shifts from anticipated shifts. We would need a computer for each atom, all of which were to work simultaneously. Perhaps, someone has thought to do that already.
Proteins fold very quickly. Intuitively I'd like to think that they begin folding as they are being formed. Simple ones may form secondary structures and find their final position in what would seemingly be one fluid motion. To do that, we have to find and compute all of the forces at work. We're still missing some important ones.
What do you think?