To add to the GP, there are at least two more fundamental problems with the computational approach: - chaperones. Not all proteins fold by themselves, quite a

To add to the GP, there are at least two more fundamental problems with the computational approach: - chaperones. Not all proteins fold by themselves, quite a few bind to an additional protein that helps them fold in the desired shape. It means that the final state is impossible to achieve from the "initial" state by gradient descent. - proteins don't necessarily exist in the minimum potential energy state. Moreover, sometimes the state flips on addition of a ligand (e.g. myosin's relationship with ATP) and that's crucial for the protein function. So static folding only gets you so far. Unfortunately, nature is hideously complicated and "entangled", so there is a tremendous gap between even perfect protein folding and real in vitro results.