Interpreting the folding kinetics of helical proteins

The detailed mechanism of protein folding is one of the major problems in structural biology(1,2). Its solution is of practical as well as fundamental interest because of its possible role in utilizing the many sequences becoming available from genomic analysis(3). Although the Levinthal paradox(4) (namely, that a polypeptide chain can find its unique native state in spite of the astronomical number of configurations in the denatured state) has been resolved(4-7), the reasons for the differences in the folding behaviour of individual proteins remain to be elucidated. Here a C-alpha-based three-helix-bundle-like protein model with a realistic thermodynamic phase diagram is used to calculate several hundred folding trajectories. By varying a single parameter, the difference between the strength of native and non-native contacts, folding is changed from a diffusion-collision mechanism(8) to one that involves simultaneous collapse and partial secondary-structure formation, followed by reorganization to the native structure. Non-obligatory intermediates are important in the former, whereas there is an obligatory on-pathway intermediate in the latter. Our results provide a basis for understanding the range of folding behaviour that is observed in helical proteins.