Protein Folding Dynamics

The dynamics of the process of protein folding from a native to a denatured state is studied in this thesis. Chapter One consists of an introduction to the area and rational for the study of the dynamics. Chapter Two is an exploration of the static and dynamical behavior of a Spin-Glass like model of protein folding. The range of physically reasonable parameters is studied and the model is seen to reproduce the general character of experimental results. Chapter Three analyzes the properties of diffusion in a complex one dimensional potential. The mean first passage time for crossing the potential is found to be fit well by existing theoretical models. The effects of the roughness of the potential on the temperature dependence are seen to have the same form as the presence of an "Arrhenius" type barrier. Chapter four examines the implications of the work of the previous chapters on the folding transition in proteins, and details the experimental results available for comparison with the model. It is found that the limiting factor in protein folding is "diffusive" searching for the native state rather than a single rate limiting step. Because of this increasing the stability of the folded state has little beneficial effect on the folding rate and can in fact slow the process by increasing the stability of local minima on the folding pathway thus inhibiting diffusive searching. An optimal window of stability of 5-30 kcal/mole is therefore found to exist where folding will occur in a biologically relevant time scale. In this chapter the model is applied to fit the experimental data on folding stability and rates for various proteins and is found to replicate the experimental results for physically reasonable parameter choices, adding credibility to the assertion that the model accurately represents physical behavior.