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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. ## Back to the list of abstracts