A kinetic theory of tertiary contact formation coupled to the helix-coil transition in polypeptides.

The framework model and the hydrophobic collapse model represent two canonical descriptions of the protein folding process. The first places primary reliance on the short-range interactions of secondary structure and the second assigns greater importance to the long-range interactions of tertiary structure. The availability of increasingly detailed information about the folding mechanisms of diverse proteins suggests that both are important and the folding mechanism of most proteins utilizes different combinations of such interactions. A prior report described the XHC model, an extended helix-coil theory, which treats the mutual stabilization of secondary and tertiary structure in simple alpha-helical proteins at equilibrium. In this study, a kinetic scheme describing tertiary contact formation has been developed which relaxes to the XHC equilibrium model. The relaxation is governed by the relative stabilities of the equilibrium states and an additional factor which represents an activation energy for formation of a tertiary contact. The model can be used to simulate time-dependent properties of the ensemble of conformations during the entire folding process, and the resulting predictions are applicable to a range of experimental methods. This XHC kinetic model enables investigation of the relative influence of secondary and tertiary interactions on folding mechanisms.