In principle couldn’t we just incorporate knowledge about chaperones into the model?
Protein structure prediction methods do the same: they find ways of restricting the conformational space to explore, in hopes of finding the global minimum-energy conformation representing the native structure of the protein.
the primary sequence is not the only consideration for proper folding.
chaperones allow higher energy folding events to occur and be maintained until subsequent modification stabilizes high energy structural motif.
chaperones also enforce an A before B before C regime of folding so that the sequence doesnt just crumple up according to energy of hydrostatic interactions
they often interact with each other, and must exert influence at proper stage of modification.
other effects beyond foldingoccur, such as addition or elimination of prosthetic groups.
the take home message is fallacy of oversimplifying the process of many molecules plus ionic enironment, interacting to influence a single molecule
the difference is akin to origami vs a crumpled ball