Visualization of unfavorable interactions in protein folds

Summary: Three dimensional structures of proteins contain errorswhich often originate from limitations of the experimental techniquesemployed. Such errors frequently result in unfavorable atomicinteractions. Here we present a new web service, called InteractionViewer, for the visualization and correction of such errors.We show how the Interaction Viewer is used in combination withthe NQ-Flipper service to spot strained asparagine and glutaminerotamers and we emphasize the convenience of this service incorrecting such errors. Availability: The web service is integrated with the NQ-Flipperservice and accessible at http://flipper.services.came.sbg.ac.at Contact: sippl{at}came.sbg.ac.at Associate Editor: Anna Tramontano     

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     

MMG: a probabilistic tool to identify submodules of metabolic pathways

Motivation: A fundamental task in systems biology is the identificationof groups of genes that are involved in the cellular responseto particular signals. At its simplest level, this often reducesto identifying biological quantities (mRNA abundance, enzymeconcentrations, etc.) which are differentially expressed intwo different conditions. Popular approaches involve using t-teststatistics, based on modelling the data as arising from a mixturedistribution. A common assumption of these approaches is thatthe data are independent and identically distributed; however,biological quantities are usually related through a complex(weighted) network of interactions, and often the more pertinentquestion is which subnetworks are differentially expressed,rather than which genes. Furthermore, in many interesting cases(such as high-throughput proteomics and metabolomics), onlyvery partial observations are available, resulting in the needfor efficient imputation techniques. Results: We introduce Mixture Model on Graphs (MMG), a novelprobabilistic model to identify differentially expressed submodulesof biological networks and pathways. The method can easily incorporateinformation about weights in the network, is robust againstmissing data and can be easily generalized to directed networks.We propose an efficient sampling strategy to infer posteriorprobabilities of differential expression, as well as posteriorprobabilities over the model parameters. We assess our methodon artificial data demonstrating significant improvements overstandard mixture model clustering. Analysis of our model resultson quantitative high-throughput proteomic data leads to theidentification of biologically significant subnetworks, as wellas the prediction of the expression level of a number of enzymes,some of which are then verified experimentally. Availability: MATLAB code is available from http://www.dcs.shef.ac.uk/~guido/software.html Contact: guido{at}dcs.shef.ac.uk Supplementary information: Supplementary data are availableat Bioinformatics online. Associate Editor: Jonathan Wren     

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     

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     

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     

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

Contact: anne.kupczok{at}univie.ac.at 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     

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     

Post-processing of BLAST results using databases of clustered sequences

Motivation: When evaluating the results of a sequence similaritysearch, there are many situations where it can be useful todetermine whether sequences appearing in the results share somedistinguishing characteristic. Such dependencies between databaseentries are often not readily identifiable, but can yield importantnew insights into the biological function of a gene or protein. Results: We have developed a program called CBLAST that sortsthe results of a BLAST sequence similarity search accordingto sequence membership in user-defined ‘clusters’of sequences. To demonstrate the utility of this application,we have constructed two cluster databases. The first describesclusters of nucleotide sequences representing the same gene,as documented in the UNIGENE database, and the second describesclusters of protein sequences which are members of the proteinfamilies documented in the PROSITE database. Cluster databasesand the CBLAST post-processor provide an efficient mechanismfor identifying and exploring relationships and dependenciesbetween new sequences and database entries. Availability: The software described in this article is availablefree of charge from the EBI software archive at < ftp: //ftp.ebi. ac. uk/pub/software/unix >. Contact: E-mail: rainer _fuchs@glaxowellcome.com     

Disease association tests by inferring ancestral haplotypes using a hidden markov model

Motivation: Most genome-wide association studies rely on singlenucleotide polymorphism (SNP) analyses to identify causal loci.The increased stringency required for genome-wide analyses (withper-SNP significance threshold typically 10^–7) meansthat many real signals will be missed. Thus it is still highlyrelevant to develop methods with improved power at low typeI error. Haplotype-based methods provide a promising approach;however, they suffer from statistical problems such as abundanceof rare haplotypes and ambiguity in defining haplotype blockboundaries. Results: We have developed an ancestral haplotype clustering(AncesHC) association method which addresses many of these problems.It can be applied to biallelic or multiallelic markers typedin haploid, diploid or multiploid organisms, and also handlesmissing genotypes. Our model is free from the assumption ofa rigid block structure but recognizes a block-like structureif it exists in the data. We employ a Hidden Markov Model (HMM)to cluster the haplotypes into groups of predicted common ancestralorigin. We then test each cluster for association with diseaseby comparing the numbers of cases and controls with 0, 1 and2 chromosomes in the cluster. We demonstrate the power of thisapproach by simulation of case-control status under a rangeof disease models for 1500 outcrossed mice originating fromeight inbred lines. Our results suggest that AncesHC has substantiallymore power than single-SNP analyses to detect disease association,and is also more powerful than the cladistic haplotype clusteringmethod CLADHC. Availability: The software can be downloaded from http://www.imperial.ac.uk/medicine/people/l.coin Contact: I.coin{at}imperial.ac.uk Supplementary Information: Supplementary data are availableat Bioinformatics online. Associate Editor: Martin Bishop     

TOPALi v2: a rich graphical interface for evolutionary analyses of multiple alignments on HPC clusters and multi-core desktops

Summary: TOPALi v2 simplifies and automates the use of severalmethods for the evolutionary analysis of multiple sequence alignments.Jobs are submitted from a Java graphical user interface as TOPALiweb services to either run remotely on high-performance computingclusters or locally (with multiple cores supported). Methodsavailable include model selection and phylogenetic tree estimationusing the Bayesian inference and maximum likelihood (ML) approaches,in addition to recombination detection methods. The optimalsubstitution model can be selected for protein or nucleic acid(standard, or protein-coding using a codon position model) datausing accurate statistical criteria derived from ML co-estimationof the tree and the substitution model. Phylogenetic softwareavailable includes PhyML, RAxML and MrBayes. Availability: Freely downloadable from http://www.topali.orgfor Windows, Mac OS X, Linux and Solaris. Contact: iain.milne{at}scri.ac.uk Associate Editor: Martin Bishop     

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     

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     

The Taverna Interaction Service: enabling manual interaction in workflows

Summary: Taverna is an application that eases the integrationof tools and databases for life science research by the constructionof workflows. The Taverna Interaction Service extends the functionalityof Taverna by defining human interaction within a workflow andacting as a mediation layer between the automated workflow engineand one or more users. Availability: Taverna, the Interaction Service plug-in and webapplication are available as open source and can be downloadedfrom http://taverna.sourceforge.net/ Contact: taverna-users{at}lists.sourceforge.net Associate Editor: John Quackenbush