KINETICS OF PROTEIN-FOLDING - NUCLEATION MECHANISM, TIME SCALES, AND PATHWAYS

The kinetics and thermodynamics of protein folding is investigated using low friction Langevin simulation of minimal continuum models of proteins. We show that the model protein has two characteristic temperatures: (a) T-theta, at which the chain undergoes a collapse transition from an extended conformation; (b) T-f(< T-theta), at which a finite size first-order transition to the folded state takes place. The kinetics of approach to the native state from initially denatured conformations is probed by several novel correlation functions. We find that the overall kinetics of approach to the native conformation occurs via a three-stage multiple pathway mechanism. The initial stage, characterized by a series of local dihedral angle transitions, eventually results in the compaction of the protein. Subsequently, the molecule acquires native-like structures during the second stage of folding. The final stage of folding involves activated transitions from one of the native-like structures to the native conformation. The first two stages are characterized by a multiplicity of pathways while relatively few paths are involved in the final stage. A detailed analysis of the dynamics of individual trajectories reveals a novel picture of protein folding. We find that a fraction of the initial population reaches the native conformation without the formation of any detectable intermediates. This pathway is associated with a nucleation mechanism, i.e., once a critical number of tertiary contacts ave established then the native state is reached rapidly. The remaining fraction of molecules become trapped in misfolded structures (stabilized by incorrect tertiary contacts). The slow folding involves transitions over barriers from these structures to the native conformation. The theoretical predictions are compared with recent experiments that probe protein folding kinetics by hydrogen exchange labeling technique. (C) 1995 John Wiley & Sons, Inc.