We suspect that there is a level of granularity of protein structure intermediate between the classical levels of 'architecture' and 'topology', as reflected in such phenomena as extensive 3D structural similarity above the level of (super)folds. Here, we examine this notion of architectural identity despite topological variability, starting with a concept that we call the 'Urfold'. We believe that this model could offer a new conceptual approach for protein structural analysis and classification: indeed, the Urfold concept may help reconcile various phenomena that have been frequently recognized or debated for years, such as the precise meaning of 'significant' structural overlap and the degree of continuity of fold space. More broadly, the role of structural similarity in sequence/structure/function evolution has been studied via many models over the years; the Urfold may help synthesize these models into a generalized, consistent framework, by addressing a conceptual gap that we believe exists between the architecture and topology levels of structural classification schemes.
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