First passage time analysis of protein folding via nucleation and of barrierless protein denaturation.

A review of the kinetic models, recently developed by the authors for the nucleation mechanism of protein folding and for the barrierless thermal denaturation, is presented. Both models are based on the mean first passage time analysis. A protein is treated as a random heteropolymer consisting of hydrophobic, hydrophilic, or neutral beads. As a crucial idea of the model, an overall potential around the cluster of native residues wherein a residue performs a chaotic motion is considered as the combination of the average dihedral, effective pairwise, and confining potentials. The overall potential as a function of the distance from the cluster center has a double well shape which allows one to determine its emission and absorption rates by the first passage time analysis. One can thus develop a theory for the nucleation mechanism of protein folding and calculate the temperature dependence of the folding time. A kinetic model for protein denaturation occurring in a barrierless way has been also developed by using the same approach. The numerical calculations for two model proteins (one consisting of 124 amino acids and the other of 2500 amino acids) demonstrate that the models can predict folding and unfolding times consistent with experimental data.