Proteins fold through a series of intermediate states called a pathway. Protein folding pathways have been modeled using either simulations or a heirarchy of statistical models. Here we present a series of related statistical models that attempt to predict early, middle and late intermediates along the folding pathway. Isites motifs are discrete models for folding initiation sites. HMMSTR is a model for local structure patterns composed of I-sites motifs. HMMSTR-CM is an approach toward

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... ng motifs and groups of motifs in a contact map representation, using heuristic rules to predict contact maps either with or without the use of templates. We also discuss the I-sites/ROSETTA server, which is a folding simulation algorithm that uses a fragment library as input. The results of blind structure prediction experiments are discussed. Pathway-based predictions sometimes lead to an unambiguous prediction of the fold topology, even without using templates.