Abstract
BackgroundIdentifying structurally similar proteins with different chain topologies can aid studies in homology modeling, protein folding, protein design, and protein evolution. These include circular permuted protein structures, and the more general cases of non-cyclic permutations between similar structures, which are related by non-topological rearrangement beyond circular permutation. We present a method based on an approximation algorithm that finds sequence-order independent structural alignments that are close to optimal. We formulate the structural alignment problem as a special case of the maximum-weight independent set problem, and solve this computationally intensive problem approximately by iteratively solving relaxations of a corresponding integer programming problem. The resulting structural alignment is sequence order independent. Our method is also insensitive to insertions, deletions, and gaps.ResultsUsing a novel similarity score and a statistical model for significance p-value, we are able to discover previously unknown circular permuted proteins between nucleoplasmin-core protein and auxin binding protein, between aspartate rasemase and 3-dehydrogenate dehydralase, as well as between migration inhibition factor and arginine repressor which involves an additional strand-swapping. We also report the finding of non-cyclic permuted protein structures existing in nature between AML1/core binding factor and ribofalvin synthase. Our method can be used for large scale alignment of protein structures regardless of the topology.ConclusionThe approximation algorithm introduced in this work can find good solutions for the problem of protein structure alignment. Furthermore, this algorithm can detect topological differences between two spatially similar protein structures. The alignment between MIF and the arginine repressor demonstrates our algorithm's ability to detect structural similarities even when spatial rearrangement of structural units has occurred. The effectiveness of our method is also demonstrated by the discovery of previously unknown circular permutations. In addition, we report in this study the finding of a naturally occurring non-cyclic permuted protein between AML1/Core Binding Factor chain F and riboflavin synthase chain A.
Highlights
Identifying structurally similar proteins with different chain topologies can aid studies in homology modeling, protein folding, protein design, and protein evolution
Discovery of novel circular permutations and a novel noncyclic permutation The effectiveness of our method is demonstrated by the discovery of previously unknown circular permutations
We have discovered a novel circular permutation between the microphage migration inhibition factor (MIF, PDB ID 1uiz, chain A, from Xenopus laevis) and the C-terminal domain of arginine repressor (AR, 1xxa, chain C, from Escherichia coli) [24,25], which contains in addition to circular permutation a spatial swapping of two antiparallel strands, and a change in the orientation of a helix
Summary
Identifying structurally similar proteins with different chain topologies can aid studies in homology modeling, protein folding, protein design, and protein evolution. BMC Bioinformatics 2007, 8:388 http://www.biomedcentral.com/1471-2105/8/388 classifies proteins structures into common folds using the topological arrangement of secondary structural units [1]. Most protein structural alignment methods can reliably classify proteins into similar folds given the structural units from each protein are in the same sequential order. The evolutionary possibility of proteins with different structural topology but with similar spatial arrangement of their secondary structures pose a problem. One such possibility is the circular permutation. A circular permutation is an evolutionary event that results in the N and C terminus transferring to a different position on a protein. The jackbean-favin permutation was the result of post-translational ligation of the N and C terminus and cleavage elsewhere in the chain, a circular permutation can arise from events at the gene level through gene duplication and exon shuffling
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