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A comprehensive analysis of non-sequential alignments between all protein structures.

ABSTRACT: BACKGROUND: The majority of relations between proteins can be represented as a conventional sequential alignment. Nevertheless, unusual non-sequential alignments with different connectivity of the aligned fragments in compared proteins have been reported by many researchers. It is interesting to understand those non-sequential alignments; are they unique, sporadic cases or they occur frequently; do they belong to a few specific folds or spread among many different folds, as a common feature of protein structure. We present here a comprehensive large-scale study of non-sequential alignments between available protein structures in Protein Data Bank. RESULTS: The study has been conducted on a non-redundant set of 8,865 protein structures aligned with the aid of the TOPOFIT method. It has been estimated that between 17.4% and 35.2% of all alignments are non-sequential depending on variations in the parameters. Analysis of the data revealed that non-sequential relations between proteins do occur systematically and in large quantities. Various sizes and numbers of non-sequential fragments have been observed with all possible complexities of fragment rearrangements found for alignments consisting of up to 12 fragments. It has been found that non-sequential alignments are not limited to proteins of any particular fold and are present in more than two hundred of them. Moreover, many of them are found between proteins with different fold assignments. It has been shown that protein structure symmetry does not explain non-sequential alignments. Therefore, compelling evidences have been provided that non-sequential alignments between proteins are systematic and widespread across the protein universe. CONCLUSION: The phenomenon of the widespread occurrence of non-sequential alignments between proteins might represent a missing rule of protein structure organization. More detailed study of this phenomenon will enhance our understanding of protein stability, folding, and evolution.

SUBMITTER: Abyzov A

PROVIDER: S-EPMC2213659 | biostudies-literature | 2007

REPOSITORIES: biostudies-literature

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A comprehensive analysis of non-sequential alignments between all protein structures.

Abyzov Alexej A Ilyin Valentin A VA

BMC structural biology 20071116

<h4>Background</h4>The majority of relations between proteins can be represented as a conventional sequential alignment. Nevertheless, unusual non-sequential alignments with different connectivity of the aligned fragments in compared proteins have been reported by many researchers. It is interesting to understand those non-sequential alignments; are they unique, sporadic cases or they occur frequently; do they belong to a few specific folds or spread among many different folds, as a common featu ...[more]

PMID: 18005453

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Project description:BackgroundProtein pairs that have the same secondary structure packing arrangement but have different topologies have attracted much attention in terms of both evolution and physical chemistry of protein structures. Further investigation of such protein relationships would give us a hint as to how proteins can change their fold in the course of evolution, as well as a insight into physico-chemical properties of secondary structure packing. For this purpose, highly accurate sequence order independent structure comparison methods are needed.ResultsWe have developed a novel protein structure alignment algorithm, MICAN (a structure alignment algorithm that can handle Multiple-chain complexes, Inverse direction of secondary structures, Cα only models, Alternative alignments, and Non-sequential alignments). The algorithm was designed so as to identify the best structural alignment between protein pairs by disregarding the connectivity between secondary structure elements (SSE). One of the key feature of the algorithm is utilizing the multiple vector representation for each SSE, which enables us to correctly treat bent or twisted nature of long SSE. We compared MICAN with other 9 publicly available structure alignment programs, using both reference-dependent and reference-independent evaluation methods on a variety of benchmark test sets which include both sequential and non-sequential alignments. We show that MICAN outperforms the other existing methods for reproducing reference alignments of non-sequential test sets. Further, although MICAN does not specialize in sequential structure alignment, it showed the top level performance on the sequential test sets. We also show that MICAN program is the fastest non-sequential structure alignment program among all the programs we examined here.ConclusionsMICAN is the fastest and the most accurate program among non-sequential alignment programs we examined here. These results suggest that MICAN is a highly effective tool for automatically detecting non-trivial structural relationships of proteins, such as circular permutations and segment-swapping, many of which have been identified manually by human experts so far. The source code of MICAN is freely download-able at http://www.tbp.cse.nagoya-u.ac.jp/MICAN.

Project description:BackgroundSeveral methods are currently available for the comparison of protein structures. These methods have been analysed regarding the performance in the identification of structurally/evolutionary related proteins, but so far there has been less focus on the objective comparison between the alignments produced by different methods.ResultsWe analysed and compared the structural alignments obtained by different methods using three sets of pairs of structurally related proteins. The first set corresponds to 355 pairs of remote homologous proteins according to the SCOP database (ASTRAL40 set). The second set was derived from the SISYPHUS database and includes 69 protein pairs (SISY set). The third set consists of 40 pairs that are challenging to align (RIPC set). The alignment of pairs of this set requires indels of considerable number and size and some of the proteins are related by circular permutations, show extensive conformational variability or include repetitions. Two standard methods (CE and DALI) were applied to align the proteins in the ASTRAL40 set. The extent of structural similarity identified by both methods is highly correlated and the alignments from the two methods agree on average in more than half of the aligned positions. CE, DALI, as well as four additional methods (FATCAT, MATRAS, Calpha-match and SHEBA) were then compared using the SISY and RIPC sets. The accuracy of the alignments was assessed by comparison to reference alignments. The alignments generated by the different methods on average match more than half of the reference alignments in the SISY set. The alignments obtained in the more challenging RIPC set tend to differ considerably and match reference alignments less successfully than the SISY set alignments.ConclusionThe alignments produced by different methods tend to agree to a considerable extent, but the agreement is lower for the more challenging pairs. The results for the comparison to reference alignments are encouraging, but also indicate that there is still room for improvement.

Project description:BackgroundKnowledge of protein-DNA interactions at the structural-level can provide insights into the mechanisms of protein-DNA recognition and gene regulation. Although over 1400 protein-DNA complex structures have been deposited into Protein Data Bank (PDB), the structural details of protein-DNA interactions are generally not available. In addition, current approaches to comparison of protein-DNA complexes are mainly based on protein sequence similarity while the DNA sequences are not taken into account. With the number of experimentally-determined protein-DNA complex structures increasing, there is a need for an automatic program to analyze the protein-DNA complex structures and to provide comprehensive structural information for the benefit of the whole research community.ResultsWe developed an automatic and comprehensive protein-DNA complex structure analysis program, PDA (for protein-DNA complex structure analyzer). PDA takes PDB files as inputs and performs structural analysis that includes 1) whole protein-DNA complex structure restoration, especially the reconstruction of double-stranded DNA structures; 2) an efficient new approach for DNA base-pair detection; 3) systematic annotation of protein-DNA interactions; and 4) extraction of DNA subsequences involved in protein-DNA interactions and identification of protein-DNA binding units. Protein-DNA complex structures in current PDB were processed and analyzed with our PDA program and the analysis results were stored in a database. A dataset useful for studying protein-DNA interactions involved in gene regulation was generated using both protein and DNA sequences as well as the contact information of the complexes. WebPDA was developed to provide a web interface for using PDA and for data retrieval.ConclusionPDA is a computational tool for structural annotations of protein-DNA complexes. It provides a useful resource for investigating protein-DNA interactions. Data from the PDA analysis can also facilitate the classification of protein-DNA complexes and provide insights into rational design of benchmarks. The PDA program is freely available at http://bioinfozen.uncc.edu/webpda.

Dataset Information

A comprehensive analysis of non-sequential alignments between all protein structures.

Publications

A comprehensive analysis of non-sequential alignments between all protein structures.

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