The Folding Mechanism and Kinetics of the Domains of α-Spectrin: Results from a Variational Model

Abstract

Although the three domains of α-spectrin (R15, R16, and R17) are highly homologous, experiments reveal striking differences in their folding mechanism and kinetics. In particular, the R15 domain's folding rate is measured to be three orders of magnitude greater than the other two domains, with R17 being the slowest. Higher folding barriers as well as increased internal friction due to landscape ruggedness are proposed to be responsible for the diversity of folding rates. In this work, we show that a simple analytic model is able to capture subtleties in the folding mechanism of α-spectrin domains despite their structural similarities. Using a simple model for internal friction based on variance in native contact energies, the model also gives folding kinetics that qualitatively agree with experimental rates. The model predicts that R16 and R17 have higher folding barriers and increased internal friction within the transition state ensemble compared to R15. While the model captures the correct range of folding rates for the domains of α-spectrin, the degree that internal friction influences folding kinetics of each domain may be sensitive to molecular detail beyond the level of approximation in this simple model.