Transition states in protein folding kinetics: modeling phi-values of small beta-sheet proteins.
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 Phi-values for two small beta-sheet proteins, the PIN and the FBP WW domains. The native structure of these WW domains comprises two beta-hairpins that form a three-stranded beta-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 beta-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 Phi-values that have been difficult to interpret.
Weikl
Thomas R
TR
Max Planck Institute of Colloids and Interfaces, Department of Theory and Bio-Systems, Potsdam, Germany. weikl@mpikg.mpg.de
D003198:Computer Simulation; D008956:Models, Chemical; D008958:Models, Molecular; D044367:Phase Transition; D011487:Protein Conformation; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry* / Q000648:ultrastructure*
D011506:Proteins