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Transition States in Protein Folding Kinetics: Modeling -Values of Small β-Sheet Proteins

Max Planck Institute of Colloids and Interfaces, Department of Theory and Bio-Systems, Potsdam, Germany

Correspondence: Address reprint requests to Dr. Thomas R. Weikl, Tel.: 0-11-49-331-567-9609; E-mail: weikl{at}mpikg.mpg.de.

Small single-domain proteins often exhibit only a single free-energy barrier, or transition state, between the denatured and the native state. The folding kinetics of these proteins is usually explored via mutational analysis. A central question is which structural information on the transition state can be derived from the mutational data. In this article, we model and structurally interpret mutational -values for two small β-sheet proteins, the PIN and the FBP WW domains. The native structure of these WW domains comprises two β-hairpins that form a three-stranded β-sheet. In our model, we assume that the transition state consists of two conformations in which either one of the hairpins is formed. Such a transition state has been recently observed in molecular dynamics folding-unfolding simulations of a small designed three-stranded β-sheet protein. We obtain good agreement with the experimental data 1), by splitting up the mutation-induced free-energy changes into terms for the two hairpins and for the small hydrophobic core of the proteins; and 2), by fitting a single parameter, the relative degree to which hairpins 1 and 2 are formed in the transition state. The model helps us to understand how mutations affect the folding kinetics of WW domains, and captures also negative -values that have been difficult to interpret.