Development of a simple statistical mechanical model of protein folding kinetics

Our understanding of the principles that underlie the protein folding problem can be tested by developing and characterizing simple models that make predictions that can be compared to experimental data. Therefore, we extend our earlier model of folding free energy landscapes, in which each residue is considered to be either folded as in the native state or completely disordered, by investigating the role of additional factors representing hydrogen bonding and backbone torsion strain, and by using a hybrid between the master equation approach and the simple Transition State Theory to evaluate kinetics near the free energy barrier in greater detail. The new model predicts folding rates that, for most proteins, are within a factor of 100 to the experimentally determined rates over a one million-fold range of folding rates. The model is also used to predict folding &phis;-values for 19 proteins that have been characterized experimentally, and for more than half of these, model calculations reproduce experimental data with correlation coefficients between r = 0.41 and r = 0.88. As a more general test, we are malting available predictions of folding rates and mechanisms for a comprehensive set of small protein domains of known structure.