Prediction of folding mechanism for circular-permuted proteins

Recent theoretical and experimental studies have suggested that real protei ns have sequences with sufficiently small energetic frustration that topolo gical effects are central in determining the folding mechanism. A particula rly interesting and challenging framework for exploring and testing the via bility of these energetically unfrustrated models is the study of circular- permuted proteins. Here we present the results of the application of a topo logy-based model to the study of circular permuted SH3 and CI2, in comparis on with the available experimental results. The folding mechanism of the pe rmuted proteins emerging from our simulations is in very good agreement wit h the experimental observations. The differences between the folding mechan isms of the permuted and wild-type proteins seem then to be strongly relate d to the change in the native state topology. (C) 2001 Academic Press.