MODELS OF COOPERATIVITY IN PROTEIN-FOLDING

What is the basis for the two-state cooperativity of protein folding? Since the 1950s, three main models have been put forward. 1. In 'helix -coil' theory, cooperativity is due to local interactions among near n eighbours in the sequence. Helix-coil cooperativity is probably not th e principal basis for the folding of globular proteins because it is n ot two-state, the forces are weak, it does not account for sheet prote ins, and there is no evidence that helix formation precedes the format ion of a hydrophobic core in the folding pathways. 2. In the 'sidechai n packing' model, cooperativity is attributed to the jigsaw-puzzle-lik e complementary fits of sidechains. This too is probably not the basis of folding cooperativity because exact models and experiments on homo polymers with sidechains give no evidence that sidechain freezing is t wo-state, sidechain complementarities in proteins are only weak trends , and the molten globule model predicted by this model is far more nat ive-like than experiments indicate. 3. In the 'hydrophobic core collap se' model, cooperativity is due to the assembly of non-polar residues into a good core. Exact model studies show that this model gives two-s tate behaviour for some sequences of hydrophobic and polar monomers. I t is based on strong forces. There is considerable experimental eviden ce for the kinetics this model predicts: the development of hydrophobi c clusters and cores is concurrent with secondary structure formation. It predicts compact denatured states with sizes and degrees of disord er that are in reasonable agreement with experiments.