Comment on 'A congruence index for testing topological similarity between trees'

Contact: anne.kupczok{at}univie.ac.at Associate Editor: Martin Bishop     

A note on difficult structure alignment problems

Progress in structural biology depends on several key technologies. In particular tools for alignment and superposition of protein structures are indispensable. Here we describe the use of the TopMatch web service, an effective computational tool for protein structure alignment, for the visualization of structural similarities, and for highlighting relationships found in protein classifications. We provide several instructive examples. AVAILABILITY: TopMatch is available as a public web service at http://services.came.sbg.ac.at.     

DNAPlotter: circular and linear interactive genome visualization

Summary: DNAPlotter is an interactive Java application for generatingcircular and linear representations of genomes. Making use ofthe Artemis libraries to provide a user-friendly method of loadingin sequence files (EMBL, GenBank, GFF) as well as data fromrelational databases, it filters features of interest to displayon separate user-definable tracks. It can be used to producepublication quality images for papers or web pages. Availability: DNAPlotter is freely available (under a GPL licence)for download (for MacOSX, UNIX and Windows) at the WellcomeTrust Sanger Institute web sites: http://www.sanger.ac.uk/Software/Artemis/circular/ Contact: artemis{at}sanger.ac.uk Associate Editor: John Quackenbush     

ConFunc--functional annotation in the twilight zone

Motivation: The success of genome sequencing has resulted inmany protein sequences without functional annotation. We presentConFunc, an automated Gene Ontology (GO)-based protein functionprediction approach, which uses conserved residues to generatesequence profiles to infer function. ConFunc split sets of sequencesidentified by PSI-BLAST into sub-alignments according to theirGO annotations. Conserved residues are identified for each GOterm sub-alignment for which a position specific scoring matrixis generated. This combination of steps produces a set of feature(GO annotation) derived profiles from which protein functionis predicted. Results: We assess the ability of ConFunc, BLAST and PSI-BLASTto predict protein function in the twilight zone of sequencesimilarity. ConFunc significantly outperforms BLAST & PSI-BLASTobtaining levels of recall and precision that are not obtainedby either method and maximum precision 24% greater than BLAST.Further for a large test set of sequences with homologues oflow sequence identity, at high levels of presicision, ConFuncobtains recall six times greater than BLAST. These results demonstratethe potential for ConFunc to form part of an automated genomicsannotation pipeline. Availability: http://www.sbg.bio.ic.ac.uk/confunc Contact: m.sternberg{at}imperial.ac.uk Supplementary information: Supplementary data are availableat Bioinformatics online. Associate Editor: Dmitrij Frishman     

A discrete view on fold space

The database of known protein structures contains an overwhelming number of structural similarities that frequently point to intriguing biological relationships. The similarities are often difficult to spot, and once detected their comprehension needs proper visualization. Here we introduce the new concept of a Fold Space Navigator, a user interface enabling the efficient navigation through fold space and the instantaneous visualization of pairwise structure similarities. AVAILABILITY: The Fold Space Navigator is accessible as a public web service at http://services.came.sbg.ac.at     

3D-Garden: a system for modelling protein-protein complexes based on conformational refinement of ensembles generated with the marching cubes algorithm

Motivation: Reliable structural modelling of protein–proteincomplexes has widespread application, from drug design to advancingour knowledge of protein interactions and function. This workaddresses three important issues in protein–protein docking:implementing backbone flexibility, incorporating prior indicationsfrom experiment and bioinformatics, and providing public accessvia a server. 3D-Garden (Global And Restrained Docking ExplorationNexus), our benchmarked and server-ready flexible docking system,allows sophisticated programming of surface patches by the uservia a facet representation of the interactors’ molecularsurfaces (generated with the marching cubes algorithm). Flexibilityis implemented as a weighted exhaustive conformer search foreach clashing pair of molecular branches in a set of 5000 modelsfiltered from around 340 000 initially. Results: In a non-global assessment, carried out strictly accordingto the protocols for number of models considered and model qualityof the Critical Assessment of Protein Interactions (CAPRI) experiment,over the widely-used Benchmark 2.0 of 84 complexes, 3D-Gardenidentifies a set of ten models containing an acceptable or bettermodel in 29/45 test cases, including one with large conformationalchange. In 19/45 cases an acceptable or better model is rankedfirst or second out of 340 000 candidates. Availability: http://www.sbg.bio.ic.ac.uk/3dgarden (server) Contact: v.lesk{at}ic.ac.uk Supplementary information: Supplementary data are availableat Bioinformatics online. Associate Editor: Burkhard Rost     

EMBL sequence submission system--an object-oriented approach to developing interactive data collection systems through the WWW

Motivation: To enable a new way of submitting sequence informationto the EMBL nucleotide database through the WWW. This processof data submission is long and complex, and calls for efficientand user-friendly mechanisms for collection and validation ofinformation. Results: Described here is a generic, object-oriented data-submissionsystem that is being used for the EMBL database, but can easilybe tailored to serve several data-submission schemes with arelatively short development and implementation time. The programprovides the user with a friendly interface that breaks thecomplex task into smaller, more manageable tasks and, on theother hand, acts as a pre-filter, scanning errors online. Availability: The program is accessible through the EMBL-EBlWWW server at the URL: http: //www.ebi.ac.uk/subs/ emblsubs.html Contact: E-mail: bshomer{at}ebi.ac.uk     

Integrating ARC grid middleware with Taverna workflows

Summary: This work presents two independent approaches for aseamless integration of computational grids with the bioinformaticsworkflow suite Taverna. These are supported by a unique relationaldatabase to link applications with grid resources and presentsthose as workflow elements. A web portal facilitates its collaborativemaintenance. The first approach implements a gateway serviceto handle authentication certificates and all communicationwith the grid. It reads the database to spawn web services forworkflow elements which are in turn used by Taverna. The secondapproach lets Taverna communicate with the grid on its own,by means of a newly developed plug-in. It reads the databaseand executes the needed tasks directly on the grid. While thegateway service is non-intrusive, the plug-in has technicaladvantages, e.g. by allowing data to remain on the grid whilebeing passed between workflow elements. Availability: http://grid.inb.uni-luebeck.de/ Contact: bayer{at}inb.uni-luebeck.de Associate Editor: Alfonso Valencia     

CRONOS: the cross-reference navigation server

Summary: Cross-mapping of gene and protein identifiers betweendifferent databases is a tedious and time-consuming task. Toovercome this, we developed CRONOS, a cross-reference serverthat contains entries from five mammalian organisms presentedby major gene and protein information resources. Sequence similarityanalysis of the mapped entries shows that the cross-referencesare highly accurate. In total, up to 18 different identifiertypes can be used for identification of cross-references. Thequality of the mapping could be improved substantially by exclusionof ambiguous gene and protein names which were manually validated.Organism-specific lists of ambiguous terms, which are valuablefor a variety of bioinformatics applications like text miningare available for download. Availability: CRONOS is freely available to non-commercial usersat http://mips.gsf.de/genre/proj/cronos/index.html, web servicesare available at http://mips.gsf.de/CronosWSService/CronosWS?wsdl. Contact: brigitte.waegele{at}helmholtz-muenchen.de Supplementary information: Supplementary data are availableat Bioinformatics online. The online Supplementary Materialcontains all figures and tables referenced by this article. Associate Editor: Martin Bishop     

ISD: a software package for Bayesian NMR structure calculation

Summary: The conventional approach to calculating biomolecularstructures from nuclear magnetic resonance (NMR) data is oftenviewed as subjective due to its dependence on rules of thumbfor deriving geometric constraints and suitable values for theoryparameters from noisy experimental data. As a result, it canbe difficult to judge the precision of an NMR structure in anobjective manner. The inferential Structure determination (ISD)framework, which has been introduced recently, addresses thisproblem by using Bayesian inference to derive a probabilitydistribution that represents both the unknown structure andits uncertainty. It also determines additional unknowns, suchas theory parameters, that normally need to be chosen empirically.Here we give an overview of the ISD software package, whichimplements this methodology. Availability: http://www.bioc.cam.ac.uk/isd Contact: wolfgang.rieping{at}bioc.cam.ac.uk, michael.habeck{at}tuebingen.mpg.de Associate Editor: Alfonso Valencia     

Model-based analysis of non-specific binding for background correction of high-density oligonucleotide microarrays

Motivation: High-density DNA microarrays provide us with usefultools for analyzing DNA and RNA comprehensively. However, thebackground signal caused by the non-specific binding (NSB) betweenprobe and target makes it difficult to obtain accurate measurements.To remove the background signal, there is a set of backgroundprobes on Affymetrix Exon arrays to represent the amount ofnon-specific signals, and an accurate estimation of non-specificsignals using these background probes is desirable for improvementof microarray analyses. Results: We developed a thermodynamic model of NSB on shortnucleotide microarrays in which the NSBs are modeled by duplexformation of probes and multiple hypothetical targets. We fittedthe observed signal intensities of the background probes withthose expected by the model to obtain the model parameters.As a result, we found that the presented model can improve theaccuracy of prediction of non-specific signals in comparisonwith previously proposed methods. This result will provide auseful method to correct for the background signal in oligonucleotidemicroarray analysis. Availability: The software is implemented in the R languageand can be downloaded from our website (http://www-shimizu.ist.osaka-u.ac.jp/shimizu_lab/MSNS/). Contact: furusawa{at}ist.osaka-u.ac.jp Supplementary information: Supplementary data are availableat Bioinformatics online. The authors wish it to be known that, in their opinion, thefirst two authors should be regarded as joint First Authors. Associate Editor: Trey Ideker     

RANKPROP: a web server for protein remote homology detection

Summary: We present a large-scale implementation of the RANKPROPprotein homology ranking algorithm in the form of an openlyaccessible web server. We use the NRDB40 PSI-BLAST all-versus-allprotein similarity network of 1.1 million proteins to constructthe graph for the RANKPROP algorithm, whereas previously, resultswere only reported for a database of 108 000 proteins. We alsodescribe two algorithmic improvements to the original algorithm,including propagation from multiple homologs of the query andbetter normalization of ranking scores, that lead to higheraccuracy and to scores with a probabilistic interpretation. Availability: The RANKPROP web server and source code are availableat http://rankprop.gs.washington.edu Contact: iain{at}nec-labs.com; noble{at}gs.washington.edu Associate Editor: Burkhard Rost     

GENESIS: genome evolution scenarios

Summary: We implemented a software tool called GENESIS for threedifferent genome rearrangement problems: Sorting a unichromosomalgenome by weighted reversals and transpositions (SwRT), sortinga multichromosomal genome by reversals, translocations, fusionsand fissions (SRTl), and sorting a multichromosomal genome byweighted reversals, translocations, fusions, fissions and transpositions(SwRTTl). Availability: Source code can be obtained by the authors, oruse the web interface http://www.uni-ulm.de/in/theo/research/genesis.html Contact: simon.gog{at}uni-ulm.de Associate Editor: Chris Stoeckert     

High-performance signal peptide prediction based on sequence alignment techniques

The accuracy of current signal peptide predictors is outstanding. The most successful predictors are based on neural networks and hidden Markov models, reaching a sensitivity of 99% and an accuracy of 95%. Here, we demonstrate that the popular BLASTP alignment tool can be tuned for signal peptide prediction reaching the same high level of prediction success. Alignment-based techniques provide additional benefits. In spite of high success rates signal peptide predictors yield false predictions. Simple sequences like polyvaline, for example, are predicted as signal peptides. The general architecture of learning systems makes it difficult to trace the cause of such problems. This kind of false predictions can be recognized or avoided altogether by using sequence comparison techniques. Based on these results we have implemented a public web service, called Signal-BLAST. Predictions returned by Signal-BLAST are transparent and easy to analyze. AVAILABILITY: Signal-BLAST is available online at http://sigpep.services.came.sbg.ac.at/signalblast.html.     

QSCOP--SCOP quantified by structural relationships

The database SCOP (Structural Classification Of Proteins) has become a major resource in bioinformatics and protein science. A particular strength of SCOP is the flexibility of its rules enabling the preservation of the many details spotted by experts in the classification process. Here we endow classic SCOP Families with quantified structural information and comment on the structural diversity found in the SCOP hierarchy. Availability: Quantified SCOP (QSCOP) is available as a public WEB service. http://services.came.sbg.ac.at.     

Automated image alignment for 2D gel electrophoresis in a high-throughput proteomics pipeline

Motivation: The quest for high-throughput proteomics has revealeda number of challenges in recent years. Whilst substantial improvementsin automated protein separation with liquid chromatography andmass spectrometry (LC/MS), aka ‘shotgun’ proteomics,have been achieved, large-scale open initiatives such as theHuman Proteome Organization (HUPO) Brain Proteome Project haveshown that maximal proteome coverage is only possible when LC/MSis complemented by 2D gel electrophoresis (2-DE) studies. Moreover,both separation methods require automated alignment and differentialanalysis to relieve the bioinformatics bottleneck and so makehigh-throughput protein biomarker discovery a reality. The purposeof this article is to describe a fully automatic image alignmentframework for the integration of 2-DE into a high-throughputdifferential expression proteomics pipeline. Results: The proposed method is based on robust automated imagenormalization (RAIN) to circumvent the drawbacks of traditionalapproaches. These use symbolic representation at the very earlystages of the analysis, which introduces persistent errors dueto inaccuracies in modelling and alignment. In RAIN, a third-ordervolume-invariant B-spline model is incorporated into a multi-resolutionschema to correct for geometric and expression inhomogeneityat multiple scales. The normalized images can then be compareddirectly in the image domain for quantitative differential analysis.Through evaluation against an existing state-of-the-art methodon real and synthetically warped 2D gels, the proposed analysisframework demonstrates substantial improvements in matchingaccuracy and differential sensitivity. High-throughput analysisis established through an accelerated GPGPU (general purposecomputation on graphics cards) implementation. Availability: Supplementary material, software and images usedin the validation are available at http://www.proteomegrid.org/rain/ Contact: g.z.yang{at}imperial.ac.uk Supplementary information: Supplementary data are availableat Bioinformatics online. Associate Editor: David Rocke     

ParCrys: a Parzen window density estimation approach to protein crystallization propensity prediction

The ability to rank proteins by their likely success in crystallizationis useful in current Structural Biology efforts and in particularin high-throughput Structural Genomics initiatives. We presentParCrys, a Parzen Window approach to estimate a protein's propensityto produce diffraction-quality crystals. The Protein Data Bank(PDB) provided training data whilst the databases TargetDB andPepcDB were used to define feature selection data as well astest data independent of feature selection and training. ParCrysoutperforms the OB-Score, SECRET and CRYSTALP on the data examined,with accuracy and Matthews correlation coefficient values of79.1% and 0.582, respectively (74.0% and 0.227, respectively,on data with a ‘real-world’ ratio of positive:negativeexamples). ParCrys predictions and associated data are availablefrom www.compbio.dundee.ac.uk/parcrys. Contact: geoff{at}compbio.dundee.ac.uk Supplementary information: Supplementary data are availableat Bioinformatics online. Associate Editor: John Quackenbush