Flexible Secondary Structure Based Protein Structure Comparison Applied to the Detection of Circular Permutation

We present a novel method for structural comparison of protein structures. The approach consists of two main phases: 1) an initial search phase where, starting from aligned pairs of secondary structure elements, the space of 3D transformations is searched for similarities and 2) a subsequent refinement phase where interim solutions are subjected to parallel, local, iterative dynamic programming in the areas of possible improvement. The proposed method combines dynamic programming for finding alignments but does not restrict solutions to be sequential. In addition, to deal with the problem of nonuniqueness of optimal similarities, we introduce a consensus scoring method in selecting the preferred similarity and provide a list of top-ranked solutions. The method, called FASE (flexible alignment of secondary structure elements), was tested on well-known data and various standard problems from the literature. The results show that FASE is able to find remote and weak similarities consistently using a reasonable run time. The method was tested (using the SCOP database) on its ability to discriminate interfold pairs from intrafold pairs at the level of the best existing methods. The method was then applied to the problem of finding circular permutations in proteins.