mitoXplorer, a visual data mining platform to systematically analyze and visualize mitochondrial expression dynamics and mutations.

Mitochondria participate in metabolism and signaling. They adapt to the requirements of various cell types. Publicly available expression data permit to study expression dynamics of genes with mitochondrial function (mito-genes) in various cell types, conditions and organisms. Yet, we lack an easy way of extracting these data for mito-genes. Here, we introduce the visual data mining platform mitoXplorer, which integrates expression and mutation data of mito-genes with a manually curated mitochondrial interactome containing ∼1200 genes grouped in 38 mitochondrial processes. User-friendly analysis and visualization tools allow to mine mitochondrial expression dynamics and mutations across various datasets from four model species including human. To test the predictive power of mitoXplorer, we quantify mito-gene expression dynamics in trisomy 21 cells, as mitochondrial defects are frequent in trisomy 21. We uncover remarkable differences in the regulation of the mitochondrial transcriptome and proteome in one of the trisomy 21 cell lines, caused by dysregulation of the mitochondrial ribosome and resulting in severe defects in oxidative phosphorylation. With the newly developed Fiji plugin mitoMorph, we identify mild changes in mitochondrial morphology in trisomy 21. Taken together, mitoXplorer (http://mitoxplorer.ibdm.univ-mrs.fr) is a user-friendly, web-based and freely accessible software, aiding experimental scientists to quantify mitochondrial expression dynamics.

High-resolution TADs reveal DNA sequences underlying genome organization in flies.

Despite an abundance of new studies about topologically associating domains (TADs), the role of genetic information in TAD formation is still not fully understood. Here we use our software, HiCExplorer (hicexplorer.readthedocs.io) to annotate >2800 high-resolution (570 bp) TAD boundaries in Drosophila melanogaster. We identify eight DNA motifs enriched at boundaries, including a motif bound by the M1BP protein, and two new boundary motifs. In contrast to mammals, the CTCF motif is only enriched on a small fraction of boundaries flanking inactive chromatin while most active boundaries contain the motifs bound by the M1BP or Beaf-32 proteins. We demonstrate that boundaries can be accurately predicted using only the motif sequences at open chromatin sites. We propose that DNA sequence guides the genome architecture by allocation of boundary proteins in the genome. Finally, we present an interactive online database to access and explore the spatial organization of fly, mouse and human genomes, available at http://chorogenome.ie-freiburg.mpg.de .

Anatomy of BioJS, an open source community for the life sciences.

BioJS is an open source software project that develops visualization tools for different types of biological data. Here we report on the factors that influenced the growth of the BioJS user and developer community, and outline our strategy for building on this growth. The lessons we have learned on BioJS may also be relevant to other open source software projects.

Tools for visualization and analysis of molecular networks, pathways, and -omics data.

Biological pathways have become the standard way to represent the coordinated reactions and actions of a series of molecules in a cell. A series of interconnected pathways is referred to as a biological network, which denotes a more holistic view on the entanglement of cellular reactions. Biological pathways and networks are not only an appropriate approach to visualize molecular reactions. They have also become one leading method in -omics data analysis and visualization. Here, we review a set of pathway and network visualization and analysis methods and take a look at potential future developments in the field.

morFeus: a web-based program to detect remotely conserved orthologs using symmetrical best hits and orthology network scoring.

BACKGROUND: Searching the orthologs of a given protein or DNA sequence is one of the most important and most commonly used Bioinformatics methods in Biology. Programs like BLAST or the orthology search engine Inparanoid can be used to find orthologs when the similarity between two sequences is sufficiently high. They however fail when the level of conservation is low. The detection of remotely conserved proteins oftentimes involves sophisticated manual intervention that is difficult to automate. RESULTS: Here, we introduce morFeus, a search program to find remotely conserved orthologs. Based on relaxed sequence similarity searches, morFeus selects sequences based on the similarity of their alignments to the query, tests for orthology by iterative reciprocal BLAST searches and calculates a network score for the resulting network of orthologs that is a measure of orthology independent of the E-value. Detecting remotely conserved orthologs of a protein using morFeus thus requires no manual intervention. We demonstrate the performance of morFeus by comparing it to state-of-the-art orthology resources and methods. We provide an example of remotely conserved orthologs, which were experimentally shown to be functionally equivalent in the respective organisms and therefore meet the criteria of the orthology-function conjecture. CONCLUSIONS: Based on our results, we conclude that morFeus is a powerful and specific search method for detecting remotely conserved orthologs. morFeus is freely available at http://bio.biochem.mpg.de/morfeus/. Its source code is available from Sourceforge.net (https://sourceforge.net/p/morfeus/).

PsicquicGraph, a BioJS component to visualize molecular interactions from PSICQUIC servers.

SUMMARY: Protein interaction networks have become an essential tool in large-scale data analysis, integration, and the visualization of high-throughput data in the context of complex cellular networks. Many individual databases are available that provide information on binary interactions of proteins and small molecules. Community efforts such as PSICQUIC aim to unify and standardize information emanating from these public databases. Here we introduce PsicquicGraph, an open-source, web-based visualization component for molecular interactions from PSIQUIC services. AVAILABILITY: PsicquicGraph is freely available at the BioJS Registry for download and enhancement. Instructions on how to use the tool are available here http://goo.gl/kDaIgZ and the source code can be found at http://github.com/biojs/biojs and DOI: 10.5281/zenodo.7709.

BioJS: an open source standard for biological visualisation - its status in 2014.

BioJS is a community-based standard and repository of functional components to represent biological information on the web. The development of BioJS has been prompted by the growing need for bioinformatics visualisation tools to be easily shared, reused and discovered. Its modular architecture makes it easy for users to find a specific functionality without needing to know how it has been built, while components can be extended or created for implementing new functionality. The BioJS community of developers currently provides a range of functionality that is open access and freely available. A registry has been set up that categorises and provides installation instructions and testing facilities at http://www.ebi.ac.uk/tools/biojs/. The source code for all components is available for ready use at https://github.com/biojs/biojs.

KEGGViewer, a BioJS component to visualize KEGG Pathways.

SUMMARY: Signaling pathways provide essential information on complex regulatory processes within the cell. They are moreover widely used to interpret and integrate data from large-scale studies, such as expression or functional screens. We present KEGGViewer a BioJS component to visualize KEGG pathways and to allow their visual integration with functional data. AVAILABILITY: KEGGViewer is an open-source tool freely available at the BioJS Registry. Instructions on how to use the tool are available at http://goo.gl/dVeWpg and the source code can be found at http://github.com/biojs/biojs and DOI: 10.5281/zenodo.7708.

iAnn: an event sharing platform for the life sciences.

SUMMARY: We present iAnn, an open source community-driven platform for dissemination of life science events, such as courses, conferences and workshops. iAnn allows automatic visualisation and integration of customised event reports. A central repository lies at the core of the platform: curators add submitted events, and these are subsequently accessed via web services. Thus, once an iAnn widget is incorporated into a website, it permanently shows timely relevant information as if it were native to the remote site. At the same time, announcements submitted to the repository are automatically disseminated to all portals that query the system. To facilitate the visualization of announcements, iAnn provides powerful filtering options and views, integrated in Google Maps and Google Calendar. All iAnn widgets are freely available. AVAILABILITY: http://iann.pro/iannviewer CONTACT: manuel.corpas@tgac.ac.uk.

BioJS: an open source JavaScript framework for biological data visualization.

SUMMARY: BioJS is an open-source project whose main objective is the visualization of biological data in JavaScript. BioJS provides an easy-to-use consistent framework for bioinformatics application programmers. It follows a community-driven standard specification that includes a collection of components purposely designed to require a very simple configuration and installation. In addition to the programming framework, BioJS provides a centralized repository of components available for reutilization by the bioinformatics community. AVAILABILITY AND IMPLEMENTATION: http://code.google.com/p/biojs/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Proton transfer from 1,4-pentadiene to superoxide radical anion: a QTAIM analysis / Transferencia de protón desde el 1,4-pentadieno al radical anión superóxido: un análisis QTAIM / Transferência de prótons de 1,4-pentadieno o ânion radical superóxido: uma análise QTAI

We studied the bis-allylic proton transfer reaction from 1,4-pentadiene to superoxide radical anion (O2.-). Minima and transition state geometries, as well as thermochemical parameters were computed at the B3LYP/6-311+G(3df,2p) level of theory. The electronic wave functions of reactants, intermediates, and products were analyzed within the framework of the Quantum Theory of Atoms in Molecules. The results show the formation of strongly hydrogen bonded complexes between the 1,4-pentadien- 3-yl anion and the hydroperoxyl radical as the reaction products. These product complexes (PCs) are more stable than the isolated reactants and much more stable than the isolated products. This reaction occurs via pre-reactive complexes which are more stable than the PCs and the transition states. This is in agreement with the fact that the net proton transfer reaction that leads to free products is an endothermic and nonspontaneous process.

Nosotros estudiamos la reacción de transferencia de protón bis-alílico del 1,4-pentadieno al radical anión superóxido (O2.--). Las geometrías de los mínimos y de los estados de transición, así como también los parámetros termoquímicos se calcularon usando el nivel de teoría B3LYP/6-311+G(3df,2p). Las funciones de onda electrónicas de los reactantes, intermedios y productos se analizaron dentro del marco de la teoría cuántica de átomos en moléculas. Nuestros resultados muestran la formación de complejos estabilizados por enlaces de hidrógeno entre el anión 1,4pentadien-3-ilo y el radical hidroperoxilo como productos de reacción. Estos complejos producto (PCs) son más estables que los reactantes aislados y mucho más estables que los productos aislados. Esta reacción ocurre vía la formación de complejos pre-reactivos, los cuales son más estables que los PCs y los estados de transición. Estos resultados están de acuerdo con el hecho de que la reacción global de transferencia de protón que conduce a la formación de los productos libres es un proceso endotérmico y no espontáneo.

Estudou-se a reação de transferência do próton bis-alílico do 1,4-pentadieno ao radical ânion superóxido (O2.-). As geometrias dos mínimos e dos estados de transição, bem como os parâmetros termoquímicos foram calculadas utilizando o nível de teoria B3LYP/6-311+G(3df, 2p). As funçÃμes de onda eletrònica dos reagentes, intermediários e produtos foram analisadas no âmbito da teoria quântica de átomos em moléculas. Os resultados obtidos demonstram a formação de complexos estabilizados por ligaçÃμes de hidrogênio entre o ânion 1,4-pentadieno- 3-ilo e o radical hidroperoxilo como produtos de reação. Estes complexos formados como produtos (PCs) são mais estáveis do que os reagentes isolados e muito mais estáveis do que os produtos isolados. Esta reação ocorre por meio de complexos pré-reativos mais estáveis do que os PCs e os estados de transição. Estes resultados estão de acordo com o fato da reação global de transferência de próton que conduz à formação dos produtos livres, é um processo endotérmico e não espontâneo.

Dasty3, a WEB framework for DAS.

MOTIVATION: Dasty3 is a highly interactive and extensible Web-based framework. It provides a rich Application Programming Interface upon which it is possible to develop specialized clients capable of retrieving information from DAS sources as well as from data providers not using the DAS protocol. Dasty3 provides significant improvements on previous Web-based frameworks and is implemented using the 1.6 DAS specification. AVAILABILITY: Dasty3 is an open-source tool freely available at http://www.ebi.ac.uk/dasty/ under the terms of the GNU General public license. Source and documentation can be found at http://code.google.com/p/dasty/. CONTACT: hhe@ebi.ac.uk.

Variations in the electrostatic landscape of class II human leukocyte antigen molecule induced by modifications in the myelin basic protein peptide: a theoretical approach.

The receptor-ligand interactions involved in the formation of the complex between Class II Major Histocompatibility Complex molecules and antigenic peptides, which are essential for establishing an adaptive immunological response, were analyzed in the Class II Human Leukocyte Antigen (HLA)--Myelin Basic Protein (MBP) peptide complex (HLA-DRbeta1*1501-MBP) using a multipolar molecular electrostatic potential approach. The Human Leukocyte Antigen--peptide complex system was divided into four pockets together with their respective peptide fragment and the corresponding occupying amino acid was replaced by each of the remaining 19 amino acids. Partial atomic charges were calculated by a quantum chemistry approach at the Hatree Fock/3-21*G level, to study the behavior of monopole, dipole and quadrupole electrostatic multipolar moments. Two types of electrostatic behavior were distinguished in the pockets' amino acids: "anchoring" located in Pocket 1 and 4, and "recognition" located in Pocket 4 and 7. According to variations in the electrostatic landscape, pockets were ordered as: Pocket 1>Pocket 9>>Pocket 4 approximately Pocket 7 which is in agreement with the binding ability reported for Class II Major Histocompatibility Complex pockets. In the same way, amino acids occupying the polymorphic positions beta13R, beta26F, beta28D, beta9W, beta74A, beta47F and beta57D were shown to be key for this Receptor-Ligand interaction. The results show that the multipolar molecular electrostatic potential approach is appropriate for characterizing receptor-ligand interactions in the MHC-antigenic peptide complex, which could have potential implications for synthetic vaccine design.

Wave function analysis of MHC-peptide interactions.

We have carried out an analysis of the wave function data for three MHC-peptide complexes: HLA-DRbeta1*0101-HA, HLA-DRbeta1*0401-HA and HLA-DRbeta1*0401-Col. We used quantum chemistry computer programs to generate wave function coefficients for these complexes, from which we obtained both molecular and atomic orbital data for both pocket and peptide amino acids within each pocket region. From these discriminated data, interaction molecular orbitals (IMOs) were identified as those with large and similar atomic orbital coefficient contributions from both pocket and peptide amino acids. The present results correlate well with our previous research where only electrostatic moments were used to explore molecular component interactions. Furthermore, we show a quantum chemical methodology to produce more fine-grained results concerning amino acid behavior in the MHC-peptide interaction.

A theoretical analysis of HLA-DRbeta1*0301-CLIP complex using the first three multipolar moments of the electrostatic field.

Interactions between the HLA-DRbeta1*0301 molecule and several occupying peptides obtained from computational substitutions made to the CLIP peptide are studied. The exploration was carried out using a vector composed of the first three terms of the multipolar expansion of the electrostatic field, namely, charge (q), dipole (d) and quadrupole (C). Comparisons between pocket-peptide interactions established that the binding pockets for this HLA molecule are ordered in terms of their importance for binding peptides, as follows: P1 >>> P4 > P6 > P7 > P9. A set of electrostatically distinct amino acids that determine interaction stability and specificity were identified for each pocket. The beta74R residue was especially identified as being the key amino acid mediating the occupying peptide binding for pocket 4; this residue has been recently associated with Graves' disease.

Allele effects in MHC-peptide interactions: a theoretical analysis of HLA-DRbeta1*0101-HA and HLA-DRbeta1*0401-HA complexes.

HLA-DRbeta1*0101-HA and HLA-DRbeta1*0401-HA complexes are studied and compared by means of their computationally derived multipolar moments and electrostatic potentials. Changes in electrostatic potential are associated with definite pocket interaction profiles. Thus, Pocket 1 projects itself as an anchoring pocket for both complexes, in accordance with experimental results. While Pocket 4 has an anchoring profile in the HLA-DRbeta1*0101 allele, it presents itself as modulating pocket-peptide interactions in HLA-DRbeta1*0401. Pockets 6 and 7 both strongly contribute to allele specificity, with Pocket 7 being very important for HLA-DRbeta1*0401-HA. Pocket 9 acts as a "double purpose" interaction site for both alleles. It both projects itself as an anchoring pocket as well as modulating pocket-peptide interactions.

A comparative study of MHC Class-II HLA-DRbeta1*0401-Col II and HLA-DRbeta1*0101-HA complexes: a theoretical point of view.

A study was performed on the HLA-DRbeta1*0401-collagen II peptide complex using the computation of electronic multipolar variables proposed by us previously. Furthermore, these results were compared with those obtained for the HLA-DRbeta1*0101-haemaglutinin peptide complex studied by us with the same tools, confirming that Pocket 1 for this new complex is also the most important pocket for the interaction between the presenting molecule and the presented peptide. The pocket hierarchy established for HLA-DRbeta1*0401 allele was P1 >> P9 approximately P7 > P6 > P4, whilst a P1 >> P4 > P9 approximately P7>P6 pocket hierarchy was found for HLA-DRbeta1*0101, showing how the relative importance of the pockets distinguishes the two alleles. There are high correlation levels with experimental results (when possible), again confirming the validity of using calculated values for electronic multipolar variables as a useful tool for studying interactions between immune system molecules and peptides.

Quantum chemical analysis explains hemagglutinin peptide-MHC Class II molecule HLA-DRbeta1*0101 interactions.

We present a new method to explore interactions between peptides and major histocompatibility complex (MHC) molecules using the resultant vector of the three principal multipole terms of the electrostatic field expansion. Being that molecular interactions are driven by electrostatic interactions, we applied quantum chemistry methods to better understand variations in the electrostatic field of the MHC Class II HLA-DRbeta1*0101-HA complex. Multipole terms were studied, finding strong alterations of the field in Pocket 1 of this MHC molecule, and weak variations in other pockets, with Pocket 1>>Pocket 4>Pocket 9 approximately Pocket 7>Pocket 6. Variations produced by "ideal" amino acids and by other occupying amino acids were compared. Two types of interactions were found in all pockets: a strong unspecific one (global interaction) and a weak specific interaction (differential interaction). Interactions in Pocket 1, the dominant pocket for this allele, are driven mainly by the quadrupole term, confirming the idea that aromatic rings are important in these interactions. Multipolar analysis is in agreement with experimental results, suggesting quantum chemistry methods as an adequate methodology to understand these interactions.

Topological study of the periodic system.

We carried out a topological study of the Space of Chemical Elements, SCE, based on a clustering analysis of 72 elements, each one defined by a vector of 31 properties. We looked for neighborhoods, boundaries, and other topological properties of the SCE. Among the results one sees the well-known patterns of the Periodic Table and relationships such as the Singularity Principle and the Diagonal Relationship, but there appears also a robustness property of some of the better-known families of elements. Alkaline metals and Noble Gases are sets whose neighborhoods have no other elements besides themselves, whereas the topological boundary of the set of metals is formed by semimetallic elements.

Constructing a useful tool for characterizing amino acid conformers by means of quantum chemical and graph theory indices.

The aim of this work is to construct a tool to assist in the prediction of peptidic properties resulting from the exchange of two amino acids in a proteic chain. In the past others have used experimental properties for this purpose. However, the nature of these data sets severely limits their access to important properties pertaining to secondary structure, and hence the indices used cannot characterize different backbone conformers like alpha helix and beta strands, or side-chain conformations like gauche +, gauche - and trans. In this study we explore the importance of backbone and side-chain angles with regard to conformer similarity measured with theoretical properties calculated in an ab initio manner. For each of the 20 genetically encoded amino acids, we studied five conformers that correspond to alpha helical and beta strand structures, with three different side chain conformations for each, defined solely by their angles phi, psi and chi1. This methodology allowed each of the 108 conformers to be represented by a mathematical object without ambiguity. The peptidic chain was emulated using two capping models to simulate the effect of nearest neighbors. These are OHC-Xaa-NH2 and Ala-Xaa-Ala, where Xaa is the conformer of interest. We then calculated 40 ab initio quantum chemical and graph theory indices for each backbone-side-chain conformer to obtain a characterization and classification scheme. We found that: (1) while backbone structure is very important to conformer similarity, side-chain conformations do not cluster together in a top-level manner; (2) amino acids with pi electrons group together independent of backbone conformation.