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

Φ values are experimental measures of how the kinetics of protein folding is changed by single-site mutations. Φ values measure energetic quantities, but they 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 Φ values have both structural and energetic components. It also provides a natural and general interpretation of "nonclassical" Φ values (i.e., <0 or >1). The model reproduces the Φ values for 20 single-residue mutations in the α-helix of the protein CI2, including several nonclassical Φ values, in good agreement with experiments.