DOCKSCORE: a webserver for ranking protein-protein docked poses

Background

Proteins interact with a variety of other molecules such as nucleic acids, small molecules and other proteins inside the cell. Structure-determination of protein-protein complexes is challenging due to several reasons such as the large molecular weights of these macromolecular complexes, their dynamic nature, difficulty in purification and sample preparation. Computational docking permits an early understanding of the feasibility and mode of protein-protein interactions. However, docking algorithms propose a number of solutions and it is a challenging task to select the native or near native pose(s) from this pool. DockScore is an objective scoring scheme that can be used to rank protein-protein docked poses. It considers several interface parameters, namely, surface area, evolutionary conservation, hydrophobicity, short contacts and spatial clustering at the interface for scoring.

Results

We have implemented DockScore in form of a webserver for its use by the scientific community. DockScore webserver can be employed, subsequent to docking, to perform scoring of the docked solutions, starting from multiple poses as inputs. The results, on scores and ranks for all the poses, can be downloaded as a csv file and graphical view of the interface of best ranking poses is possible.

Conclusions

The webserver for DockScore is made freely available for the scientific community at: http://caps.ncbs.res.in/dockscore/.

Electronic supplementary material

The online version of this article (doi:10.1186/s12859-015-0572-6) contains supplementary material, which is available to authorized users.     

Presaging Critical Residues in Protein interfaces-Web Server (PCRPi-W): A Web Server to Chart Hot Spots in Protein Interfaces

Background

It is well established that only a portion of residues that mediate protein-protein interactions (PPIs), the so-called hot spot, contributes the most to the total binding energy, and thus its identification is an important and relevant question that has clear applications in drug discovery and protein design. The experimental identification of hot spots is however a lengthy and costly process, and thus there is an interest in computational tools that can complement and guide experimental efforts.

Principal Findings

Here, we present Presaging Critical Residues in Protein interfaces-Web server (http://www.bioinsilico.org/PCRPi), a web server that implements a recently described and highly accurate computational tool designed to predict critical residues in protein interfaces: PCRPi. PRCPi depends on the integration of structural, energetic, and evolutionary-based measures by using Bayesian Networks (BNs).

Conclusions

PCRPi-W has been designed to provide an easy and convenient access to the broad scientific community. Predictions are readily available for download or presented in a web page that includes among other information links to relevant files, sequence information, and a Jmol applet to visualize and analyze the predictions in the context of the protein structure.     

Enhancing protein-vitamin binding residues prediction by multiple heterogeneous subspace SVMs ensemble

Background

Vitamins are typical ligands that play critical roles in various metabolic processes. The accurate identification of the vitamin-binding residues solely based on a protein sequence is of significant importance for the functional annotation of proteins, especially in the post-genomic era, when large volumes of protein sequences are accumulating quickly without being functionally annotated.

Results

In this paper, a new predictor called TargetVita is designed and implemented for predicting protein-vitamin binding residues using protein sequences. In TargetVita, features derived from the position-specific scoring matrix (PSSM), predicted protein secondary structure, and vitamin binding propensity are combined to form the original feature space; then, several feature subspaces are selected by performing different feature selection methods. Finally, based on the selected feature subspaces, heterogeneous SVMs are trained and then ensembled for performing prediction.

Conclusions

The experimental results obtained with four separate vitamin-binding benchmark datasets demonstrate that the proposed TargetVita is superior to the state-of-the-art vitamin-specific predictor, and an average improvement of 10% in terms of the Matthews correlation coefficient (MCC) was achieved over independent validation tests. The TargetVita web server and the datasets used are freely available for academic use at http://csbio.njust.edu.cn/bioinf/TargetVita or http://www.csbio.sjtu.edu.cn/bioinf/TargetVita.

Electronic supplementary material

The online version of this article (doi:10.1186/1471-2105-15-297) contains supplementary material, which is available to authorized users.     

BACA: bubble chArt to compare annotations

Background

DAVID is the most popular tool for interpreting large lists of gene/proteins classically produced in high-throughput experiments. However, the use of DAVID website becomes difficult when analyzing multiple gene lists, for it does not provide an adequate visualization tool to show/compare multiple enrichment results in a concise and informative manner.

Result

We implemented a new R-based graphical tool, BACA (Bubble chArt to Compare Annotations), which uses the DAVID web service for cross-comparing enrichment analysis results derived from multiple large gene lists. BACA is implemented in R and is freely available at the CRAN repository (http://cran.r-project.org/web/packages/BACA/).

Conclusion

The package BACA allows R users to combine multiple annotation charts into one output graph by passing DAVID website.

Electronic supplementary material

The online version of this article (doi:10.1186/s12859-015-0477-4) contains supplementary material, which is available to authorized users.     

MendeLIMS: a web-based laboratory information management system for clinical genome sequencing

Background

Large clinical genomics studies using next generation DNA sequencing require the ability to select and track samples from a large population of patients through many experimental steps. With the number of clinical genome sequencing studies increasing, it is critical to maintain adequate laboratory information management systems to manage the thousands of patient samples that are subject to this type of genetic analysis.

Results

To meet the needs of clinical population studies using genome sequencing, we developed a web-based laboratory information management system (LIMS) with a flexible configuration that is adaptable to continuously evolving experimental protocols of next generation DNA sequencing technologies. Our system is referred to as MendeLIMS, is easily implemented with open source tools and is also highly configurable and extensible. MendeLIMS has been invaluable in the management of our clinical genome sequencing studies.

Conclusions

We maintain a publicly available demonstration version of the application for evaluation purposes at http://mendelims.stanford.edu. MendeLIMS is programmed in Ruby on Rails (RoR) and accesses data stored in SQL-compliant relational databases. Software is freely available for non-commercial use at http://dna-discovery.stanford.edu/software/mendelims/.

Electronic supplementary material

The online version of this article (doi:10.1186/1471-2105-15-290) contains supplementary material, which is available to authorized users.     

Inferring copy number and genotype in tumour exome data

Background

Using whole exome sequencing to predict aberrations in tumours is a cost effective alternative to whole genome sequencing, however is predominantly used for variant detection and infrequently utilised for detection of somatic copy number variation.

Results

We propose a new method to infer copy number and genotypes using whole exome data from paired tumour/normal samples. Our algorithm uses two Hidden Markov Models to predict copy number and genotypes and computationally resolves polyploidy/aneuploidy, normal cell contamination and signal baseline shift. Our method makes explicit detection on chromosome arm level events, which are commonly found in tumour samples. The methods are combined into a package named ADTEx (Aberration Detection in Tumour Exome). We applied our algorithm to a cohort of 17 in-house generated and 18 TCGA paired ovarian cancer/normal exomes and evaluated the performance by comparing against the copy number variations and genotypes predicted using Affymetrix SNP 6.0 data of the same samples. Further, we carried out a comparison study to show that ADTEx outperformed its competitors in terms of precision and F-measure.

Conclusions

Our proposed method, ADTEx, uses both depth of coverage ratios and B allele frequencies calculated from whole exome sequencing data, to predict copy number variations along with their genotypes. ADTEx is implemented as a user friendly software package using Python and R statistical language. Source code and sample data are freely available under GNU license (GPLv3) at http://adtex.sourceforge.net/.

Electronic supplementary material

The online version of this article (doi:10.1186/1471-2164-15-732) contains supplementary material, which is available to authorized users.     

Personalized Oncology Suite: integrating next-generation sequencing data and whole-slide bioimages

Background

Cancer immunotherapy has recently entered a remarkable renaissance phase with the approval of several agents for treatment. Cancer treatment platforms have demonstrated profound tumor regressions including complete cure in patients with metastatic cancer. Moreover, technological advances in next-generation sequencing (NGS) as well as the development of devices for scanning whole-slide bioimages from tissue sections and image analysis software for quantitation of tumor-infiltrating lymphocytes (TILs) allow, for the first time, the development of personalized cancer immunotherapies that target patient specific mutations. However, there is currently no bioinformatics solution that supports the integration of these heterogeneous datasets.

Results

We have developed a bioinformatics platform – Personalized Oncology Suite (POS) – that integrates clinical data, NGS data and whole-slide bioimages from tissue sections. POS is a web-based platform that is scalable, flexible and expandable. The underlying database is based on a data warehouse schema, which is used to integrate information from different sources. POS stores clinical data, genomic data (SNPs and INDELs identified from NGS analysis), and scanned whole-slide images. It features a genome browser as well as access to several instances of the bioimage management application Bisque. POS provides different visualization techniques and offers sophisticated upload and download possibilities. The modular architecture of POS allows the community to easily modify and extend the application.

Conclusions

The web-based integration of clinical, NGS, and imaging data represents a valuable resource for clinical researchers and future application in medical oncology. POS can be used not only in the context of cancer immunology but also in other studies in which NGS data and images of tissue sections are generated. The application is open-source and can be downloaded at http://www.icbi.at/POS.

Electronic supplementary material

The online version of this article (doi:10.1186/1471-2105-15-306) contains supplementary material, which is available to authorized users.     

AKE - the Accelerated k-mer Exploration web-tool for rapid taxonomic classification and visualization

Background

With the advent of low cost, fast sequencing technologies metagenomic analyses are made possible. The large data volumes gathered by these techniques and the unpredictable diversity captured in them are still, however, a challenge for computational biology.

Results

In this paper we address the problem of rapid taxonomic assignment with small and adaptive data models (< 5 MB) and present the accelerated k-mer explorer (AKE). Acceleration in AKE’s taxonomic assignments is achieved by a special machine learning architecture, which is well suited to model data collections that are intrinsically hierarchical. We report classification accuracy reasonably well for ranks down to order, observed on a study on real world data (Acid Mine Drainage, Cow Rumen).

Conclusion

We show that the execution time of this approach is orders of magnitude shorter than competitive approaches and that accuracy is comparable. The tool is presented to the public as a web application (url: https://ani.cebitec.uni-bielefeld.de/ake/, username: bmc, password: bmcbioinfo).

Electronic supplementary material

The online version of this article (doi:10.1186/s12859-014-0384-0) contains supplementary material, which is available to authorized users.     

Sealer: a scalable gap-closing application for finishing draft genomes

Background

While next-generation sequencing technologies have made sequencing genomes faster and more affordable, deciphering the complete genome sequence of an organism remains a significant bioinformatics challenge, especially for large genomes. Low sequence coverage, repetitive elements and short read length make de novo genome assembly difficult, often resulting in sequence and/or fragment “gaps” – uncharacterized nucleotide (N) stretches of unknown or estimated lengths. Some of these gaps can be closed by re-processing latent information in the raw reads. Even though there are several tools for closing gaps, they do not easily scale up to processing billion base pair genomes.

Results

Here we describe Sealer, a tool designed to close gaps within assembly scaffolds by navigating de Bruijn graphs represented by space-efficient Bloom filter data structures. We demonstrate how it scales to successfully close 50.8 % and 13.8 % of gaps in human (3 Gbp) and white spruce (20 Gbp) draft assemblies in under 30 and 27 h, respectively – a feat that is not possible with other leading tools with the breadth of data used in our study.

Conclusion

Sealer is an automated finishing application that uses the succinct Bloom filter representation of a de Bruijn graph to close gaps in draft assemblies, including that of very large genomes. We expect Sealer to have broad utility for finishing genomes across the tree of life, from bacterial genomes to large plant genomes and beyond. Sealer is available for download at https://github.com/bcgsc/abyss/tree/sealer-release.

Electronic supplementary material

The online version of this article (doi:10.1186/s12859-015-0663-4) contains supplementary material, which is available to authorized users.     

ProteinVolume: calculating molecular van der Waals and void volumes in proteins

Background

Voids and cavities in the native protein structure determine the pressure unfolding of proteins. In addition, the volume changes due to the interaction of newly exposed atoms with solvent upon protein unfolding also contribute to the pressure unfolding of proteins. Quantitative understanding of these effects is important for predicting and designing proteins with predefined response to changes in hydrostatic pressure using computational approaches. The molecular surface volume is a useful metric that describes contribution of geometrical volume, which includes van der Waals volume and volume of the voids, to the total volume of a protein in solution, thus isolating the effects of hydration for separate calculations.

Results

We developed ProteinVolume, a highly robust and easy-to-use tool to compute geometric volumes of proteins. ProteinVolume generates the molecular surface of a protein and uses an innovative flood-fill algorithm to calculate the individual components of the molecular surface volume, van der Waals and intramolecular void volumes. ProteinVolume is user friendly and is available as a web-server or a platform-independent command-line version.

Conclusions

ProteinVolume is a highly accurate and fast application to interrogate geometric volumes of proteins. ProteinVolume is a free web server available on http://gmlab.bio.rpi.edu. Free-standing platform-independent Java-based ProteinVolume executable is also freely available at this web site.

Electronic supplementary material

The online version of this article (doi:10.1186/s12859-015-0531-2) contains supplementary material, which is available to authorized users.     

MCMC implementation of the optimal Bayesian classifier for non-Gaussian models: model-based RNA-Seq classification

Background

Sequencing datasets consist of a finite number of reads which map to specific regions of a reference genome. Most effort in modeling these datasets focuses on the detection of univariate differentially expressed genes. However, for classification, we must consider multiple genes and their interactions.

Results

Thus, we introduce a hierarchical multivariate Poisson model (MP) and the associated optimal Bayesian classifier (OBC) for classifying samples using sequencing data. Lacking closed-form solutions, we employ a Monte Carlo Markov Chain (MCMC) approach to perform classification. We demonstrate superior or equivalent classification performance compared to typical classifiers for two synthetic datasets and over a range of classification problem difficulties. We also introduce the Bayesian minimum mean squared error (MMSE) conditional error estimator and demonstrate its computation over the feature space. In addition, we demonstrate superior or leading class performance over an RNA-Seq dataset containing two lung cancer tumor types from The Cancer Genome Atlas (TCGA).

Conclusions

Through model-based, optimal Bayesian classification, we demonstrate superior classification performance for both synthetic and real RNA-Seq datasets. A tutorial video and Python source code is available under an open source license at http://bit.ly/1gimnss.

Electronic supplementary material

The online version of this article (doi:10.1186/s12859-014-0401-3) contains supplementary material, which is available to authorized users.     

Gene set enrichment analysis for multiple continuous phenotypes

Background

Gene set analysis (GSA) methods test the association of sets of genes with phenotypes in gene expression microarray studies. While GSA methods on a single binary or categorical phenotype abounds, little attention has been paid to the case of a continuous phenotype, and there is no method to accommodate correlated multiple continuous phenotypes.

Result

We propose here an extension of the linear combination test (LCT) to its new version for multiple continuous phenotypes, incorporating correlations among gene expressions of functionally related gene sets, as well as correlations among multiple phenotypes. Further, we extend our new method to its nonlinear version, referred as nonlinear combination test (NLCT), to test potential nonlinear association of gene sets with multiple phenotypes. Simulation study and a real microarray example demonstrate the practical aspects of the proposed methods.

Conclusion

The proposed approaches are effective in controlling type I errors and powerful in testing associations between gene-sets and multiple continuous phenotypes. They are both computationally effective. Naively (univariately) analyzing a group of multiple correlated phenotypes could be dangerous. R-codes to perform LCT and NLCT for multiple continuous phenotypes are available at http://www.ualberta.ca/~yyasui/homepage.html.

Electronic supplementary material

The online version of this article (doi:10.1186/1471-2105-15-260) contains supplementary material, which is available to authorized users.     

An efficiency analysis of high-order combinations of gene–gene interactions using multifactor-dimensionality reduction

Background

Multifactor dimensionality reduction (MDR) is widely used to analyze interactions of genes to determine the complex relationship between diseases and polymorphisms in humans. However, the astronomical number of high-order combinations makes MDR a highly time-consuming process which can be difficult to implement for multiple tests to identify more complex interactions between genes. This study proposes a new framework, named fast MDR (FMDR), which is a greedy search strategy based on the joint effect property.

Results

Six models with different minor allele frequencies (MAFs) and different sample sizes were used to generate the six simulation data sets. A real data set was obtained from the mitochondrial D-loop of chronic dialysis patients. Comparison of results from the simulation data and real data sets showed that FMDR identified significant gene–gene interaction with less computational complexity than the MDR in high-order interaction analysis.

Conclusion

FMDR improves the MDR difficulties associated with the computational loading of high-order SNPs and can be used to evaluate the relative effects of each individual SNP on disease susceptibility. FMDR is freely available at http://bioinfo.kmu.edu.tw/FMDR.rar.

Electronic supplementary material

The online version of this article (doi:10.1186/s12864-015-1717-8) contains supplementary material, which is available to authorized users.