Analysis of multiple folding routes of proteins by a coarse-grained dynamics model

Langevin dynamics of a protein molecule with Go-type potentials is develope d and used to analyze long time-scale events in the folding of cytochrome c . Several trajectories are generated, starting from random coil configurati ons and going to the native state, that are a few angstroms root mean squar e deviation (RMSD) from the native structure. The dynamics is controlled, t o a large scale, by the two terminal helices that are in contact in the nat ive state. These two helices form very early during folding, and depending on the trajectory, they either stabilize rapidly or break and re-form in go ing over steric barriers. The extended initial chain exhibits a rapid foldi ng transition into a relatively compact shape, after which the helices are reorganized in a highly correlated manner. The time of formation of residue pair contacts strongly points to the hierarchical nature of folding; i.e., secondary structure forms first, followed by rearrangements of larger leng th scales at longer times. The kinetics of formation of native contacts is also analyzed, and the onset of a stable globular configuration, referred t o as the molten globule in the literature, is identified. Predictions of th e model are compared with extensive experimental data on cytochrome c.