Dataset Information

CLIPS-1D: analysis of multiple sequence alignments to deduce for residue-positions a role in catalysis, ligand-binding, or protein structure.

ABSTRACT: BACKGROUND: One aim of the in silico characterization of proteins is to identify all residue-positions, which are crucial for function or structure. Several sequence-based algorithms exist, which predict functionally important sites. However, with respect to sequence information, many functionally and structurally important sites are hard to distinguish and consequently a large number of incorrectly predicted functional sites have to be expected. This is why we were interested to design a new classifier that differentiates between functionally and structurally important sites and to assess its performance on representative datasets. RESULTS: We have implemented CLIPS-1D, which predicts a role in catalysis, ligand-binding, or protein structure for residue-positions in a mutually exclusive manner. By analyzing a multiple sequence alignment, the algorithm scores conservation as well as abundance of residues at individual sites and their local neighborhood and categorizes by means of a multiclass support vector machine. A cross-validation confirmed that residue-positions involved in catalysis were identified with state-of-the-art quality; the mean MCC-value was 0.34. For structurally important sites, prediction quality was considerably higher (mean MCC = 0.67). For ligand-binding sites, prediction quality was lower (mean MCC = 0.12), because binding sites and structurally important residue-positions share conservation and abundance values, which makes their separation difficult. We show that classification success varies for residues in a class-specific manner. This is why our algorithm computes residue-specific p-values, which allow for the statistical assessment of each individual prediction. CLIPS-1D is available as a Web service at http://www-bioinf.uni-regensburg.de/. CONCLUSIONS: CLIPS-1D is a classifier, whose prediction quality has been determined separately for catalytic sites, ligand-binding sites, and structurally important sites. It generates hypotheses about residue-positions important for a set of homologous proteins and focuses on conservation and abundance signals. Thus, the algorithm can be applied in cases where function cannot be transferred from well-characterized proteins by means of sequence comparison.

SUBMITTER: Janda JO

PROVIDER: S-EPMC3391178 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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CLIPS-1D: analysis of multiple sequence alignments to deduce for residue-positions a role in catalysis, ligand-binding, or protein structure.

Janda Jan-Oliver JO Busch Markus M Kück Fabian F Porfenenko Mikhail M Merkl Rainer R

BMC bioinformatics 20120405

<h4>Background</h4>One aim of the in silico characterization of proteins is to identify all residue-positions, which are crucial for function or structure. Several sequence-based algorithms exist, which predict functionally important sites. However, with respect to sequence information, many functionally and structurally important sites are hard to distinguish and consequently a large number of incorrectly predicted functional sites have to be expected. This is why we were interested to design a ...[more]

PMID: 22480135

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Project description:BackgroundThe identification of functionally important residue positions is an important task of computational biology. Methods of correlation analysis allow for the identification of pairs of residue positions, whose occupancy is mutually dependent due to constraints imposed by protein structure or function. A common measure assessing these dependencies is the mutual information, which is based on Shannon's information theory that utilizes probabilities only. Consequently, such approaches do not consider the similarity of residue pairs, which may degrade the algorithm's performance. One typical algorithm is H2r, which characterizes each individual residue position k by the conn(k)-value, which is the number of significantly correlated pairs it belongs to.ResultsTo improve specificity of H2r, we developed a revised algorithm, named H2rs, which is based on the von Neumann entropy (vNE). To compute the corresponding mutual information, a matrix A is required, which assesses the similarity of residue pairs. We determined A by deducing substitution frequencies from contacting residue pairs observed in the homologs of 35 809 proteins, whose structure is known. In analogy to H2r, the enhanced algorithm computes a normalized conn(k)-value. Within the framework of H2rs, only statistically significant vNE values were considered. To decide on significance, the algorithm calculates a p-value by performing a randomization test for each individual pair of residue positions. The analysis of a large in silico testbed demonstrated that specificity and precision were higher for H2rs than for H2r and two other methods of correlation analysis. The gain in prediction quality is further confirmed by a detailed assessment of five well-studied enzymes. The outcome of H2rs and of a method that predicts contacting residue positions (PSICOV) overlapped only marginally. H2rs can be downloaded from http://www-bioinf.uni-regensburg.de.ConclusionsConsidering substitution frequencies for residue pairs by means of the von Neumann entropy and a p-value improved the success rate in identifying important residue positions. The integration of proven statistical concepts and normalization allows for an easier comparison of results obtained with different proteins. Comparing the outcome of the local method H2rs and of the global method PSICOV indicates that such methods supplement each other and have different scopes of application.

Dataset Information

CLIPS-1D: analysis of multiple sequence alignments to deduce for residue-positions a role in catalysis, ligand-binding, or protein structure.

Publications

CLIPS-1D: analysis of multiple sequence alignments to deduce for residue-positions a role in catalysis, ligand-binding, or protein structure.

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