Fig. 2.

A description of the four ‘classical’ folding mechanisms. (1) The framework model [164] suggests that local elements of secondary structure form first. These then diffuse together, collide and adhere to produce the correct tertiary structure in the rate determining step. (2) The hydrophobic collapse model [165] implies that a protein collapses rapidly around its hydrophobic side-chains, and then rearranges from the restricted conformation of this ‘molten-globule’ intermediate. (3) The nucleation propagation model [166] states that local interactions form a small amount of native secondary structure, which acts as a nucleus for the outward propagation of further native structure. (4) The nucleation condensation model [167] suggests the presence of a metastable nucleus that is unable to trigger folding until a sufficient number of stabilising long-range interactions have built up. Once this occurs, the native structure condenses so rapidly that the nucleus is not yet fully formed in the transition state.