Artefactual intemediates and broad activation barriers in protein folding
Mikael Oliveberg, Lunds University

Recent controversy about the role of populated intermediates in
protein folding emphasis the need to better characterise other events
on the folding pathway. A complication is that these involve
high-energy states which are difficult to target experimentally since
they do not accumulate kinetically. Here we explore the energetics of
high-energy states, and map out the shape of the free-energy profile
for folding of the two-state protein U1A. The analysis is based on
non-linearities in the GdnHCl-dependence of the activation energy for
unfolding, which we interpret in terms of structural changes of the
protein-folding transition state. The result suggests that U1A folds
by a high-energy pathway where most of the conformational search takes
place isoenergetically at transition-state level. This is manifested
in a very broad and flat activation barrier, the top of which covers
more than 60 % of the reaction coordinate. The interpretation favours
a folding mechanism where the pathway leading to the native protein is
determined by the sequence's ability to stabilise productive
transition states.

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