Protein folding mechanisms and energy landscape of src SH3 domain studied by a structure prediction toolbox

The global energy landscape of src SH3 domain is comprehensively explored and folding mechanisms are discussed by using a physico-chemical protein model and the reversible fragment assembly method. We found that the lowest energy structure found in simulations is quite similar to the native, an apparent free energy barrier exists between the denatured and native states, and the computed folding transition state ensemble is well consistent with experimental data. Interestingly, non-native alpha-helical contents are found at early stage of folding, which also seems to be consistent with a recent experiment. These results suggest that the fragment assembly method, originally developed for structure prediction, can be used for studying folding mechanisms as well. (C) 2004 Published by Elsevier B.V.