Phi-values in protein folding kinetics have energetic and structural components

Abstract

Phi-values are experimental measures of how the kinetics of protein folding is changed by single-site mutations. Phi-values measure energetic quantities, but are often interpreted in terms of the structures of the transition state ensemble. Here we describe a simple analytical model of the folding kinetics in terms of the formation of protein substructures. The model shows that Phi-values have both structural and energetic components. In addition, it provides a natural and general interpretation of "nonclassical" Phi-values (i.e., less than zero, or greater than one). The model reproduces the Phi-values for 20 single-residue mutations in the alpha-helix of the protein CI2, including several nonclassical Phi-values, in good agreement with experiments.