Existence of homologous proteins that fold into globally different structures signifies an alternative to the concept that structures are more conserved than sequences and demonstrates that protein structures can evolve and change, thus possibly generating new folds and topologies. Our understanding of fold changes in evolution is currently limited to a number of illustrious examples contributed by both experimental studies and computational analysis of available protein structures. Preliminary results demonstrate that structural changes in evolution are more common than is usually accepted. We were able to define four potential mechanisms of fold changes in evolution: insertion deletion/substitution of structural elements, circular permutation, strand invasion, hairpin flip/swap. It is necessary to clarify the scope of these events and to perform a comprehensive analysis of sequence and structure data to find all instances of such changes and classify them. We will undertake comprehensive homology searches for the sequences from proteins families with known structure to find statistically significant sequence similarity links between proteins with different folds. We will analyze the nature of the differences and catalogue possible mechanisms of fold changes in evolution of protein structures. Finally, we will perform in silico evolution of model proteins under functional constraints and compare the results to those deduced from the analysis of natural sequences and structures.
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