Analysis of folding kinetics for simplified model proteins

Abstract

The conformational stochastics of simplified model chains that show an apparent two-state kinetics was explored.. A fundamental question addressed in the present analysis is to understand if the folding takes place through a continuum of paths, or if a preferred pathway involving subcooperative folding events can be discerned. To this aim, the complete sets of conformations for short model chains were generated as self-avoiding walks on a square lattice. Native-like contacts have been assigned attractive potentials, and transition rates have been assigned on the basis of native-like contacts and root-mean-square deviations between conformations. The time evolution of all conformational transitions has been analyzed starting from a uniform distribution of conformations, using a master equation formalism. A key conclusion is that: (i) The lack of intermediates that define two-state kinetics does not preclude folding through a specific sequence of events. (ii) F-value analysis, a measure of the stability and change in folding kinetics due to mutation reveals that non classical F-values can arise from parallel microscopic flow processes. Negative F values result when a mutation destabilizes a slow flow channel, causing an overflow into a faster flow channel. F-values greater than one occur when mutations redirect a fast flow into a slower channel.