Background: Structural alignment is an important step in protein comparison. Well-established methods exist for solving this problem under the assumption that the structures under comparison are considered as rigid bodies. However, proteins are flexible entities often undergoing movements that alter the positions of domains or subdomains with respect to each other. Such movements can impede the identification of structural equivalences when rigid aligners are used.
Results: We introduce a new method called RAPIDO (Rapid Alignment of Proteins in terms of Domains) for the three-dimensional alignment of protein structures in the presence of conformational changes. The flexible aligner is coupled to a genetic algorithm for the identification of structurally conserved regions. RAPIDO is capable of aligning protein structures in the presence of large conformational changes. Structurally conserved regions are reliably detected even if they are discontinuous in sequence but continuous in space and can be used for superpositions revealing subtle differences.
Conclusion: RAPIDO is more sensitive than other flexible aligners when applied to cases of closely homologues proteins undergoing large conformational changes. When applied to a set of kinase structures it is able to detect similarities that are missed by other alignment algorithms. The algorithm is sufficiently fast to be applied to the comparison of large sets of protein structures.