Transition states in protein folding kinetics: modeling phi-values of small beta-sheet proteins.

Abstract:

: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.

journal_name

Biophys J

journal_title

Biophysical journal

authors

Weikl TR

doi

10.1529/biophysj.107.109868

subject

Has Abstract

pub_date

2008-02-01 00:00:00

pages

929-37

issue

3

eissn

0006-3495

issn

1542-0086

pii

S0006-3495(08)70691-X

journal_volume

94

pub_type

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