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1.  Ligand-Dependent Opening of the Multiple AMPA Receptor Conductance States: A Concerted Model 
PLoS ONE  2015;10(1):e0116616.
Modulation of the properties of AMPA receptors at the post-synaptic membrane is one of the main suggested mechanisms underlying fast synaptic transmission in the central nervous system of vertebrates. Electrophysiological recordings of single channels stimulated with agonists showed that both recombinant and native AMPA receptors visit multiple conductance states in an agonist concentration dependent manner. We propose an allosteric model of the multiple conductance states based on concerted conformational transitions of the four subunits, as an iris diaphragm. Our model predicts that the thermodynamic behaviour of the conductance states upon full and partial agonist stimulations can be described with increased affinity of receptors as they progress to higher conductance states. The model also predicts the existence of AMPA receptors in non-liganded conductive substates. However, the probability of spontaneous openings decreases with increasing conductances. Finally, we predict that the large conductance states are stabilized within the rise phase of a whole-cell EPSC in glutamatergic hippocampal neurons. Our model provides a mechanistic link between ligand concentration and conductance states that can explain thermodynamic and kinetic features of AMPA receptor gating.
doi:10.1371/journal.pone.0116616
PMCID: PMC4309570  PMID: 25629405
2.  Modulation of Calmodulin Lobes by Different Targets: An Allosteric Model with Hemiconcerted Conformational Transitions 
PLoS Computational Biology  2015;11(1):e1004063.
Calmodulin is a calcium-binding protein ubiquitous in eukaryotic cells, involved in numerous calcium-regulated biological phenomena, such as synaptic plasticity, muscle contraction, cell cycle, and circadian rhythms. It exibits a characteristic dumbell shape, with two globular domains (N- and C-terminal lobe) joined by a linker region. Each lobe can take alternative conformations, affected by the binding of calcium and target proteins.
Calmodulin displays considerable functional flexibility due to its capability to bind different targets, often in a tissue-specific fashion. In various specific physiological environments (e.g. skeletal muscle, neuron dendritic spines) several targets compete for the same calmodulin pool, regulating its availability and affinity for calcium. In this work, we sought to understand the general principles underlying calmodulin modulation by different target proteins, and to account for simultaneous effects of multiple competing targets, thus enabling a more realistic simulation of calmodulin-dependent pathways. We built a mechanistic allosteric model of calmodulin, based on an hemiconcerted framework: each calmodulin lobe can exist in two conformations in thermodynamic equilibrium, with different affinities for calcium and different affinities for each target. Each lobe was allowed to switch conformation on its own. The model was parameterised and validated against experimental data from the literature. In spite of its simplicity, a two-state allosteric model was able to satisfactorily represent several sets of experiments, in particular the binding of calcium on intact and truncated calmodulin and the effect of different skMLCK peptides on calmodulin’s saturation curve. The model can also be readily extended to include multiple targets. We show that some targets stabilise the low calcium affinity T state while others stabilise the high affinity R state. Most of the effects produced by calmodulin targets can be explained as modulation of a pre-existing dynamic equilibrium between different conformations of calmodulin’s lobes, in agreement with linkage theory and MWC-type models.
Author Summary
Calmodulin, the ubiquitous calcium-activated second messenger in eukaryotes, is an extremely versatile molecule involved in many biological processes: muscular contraction, synaptic plasticity, circadian rhythm, and cell cycle, among others. The protein is structurally organised into two globular lobes, joined by a flexible linker. Calcium modulates calmodulin activity by favoring a conformational transition of each lobe from a closed conformation to an open conformation. Most targets have a strong preference for one conformation over the other, and depending on the free calcium concentration in a cell, particular sets of targets will preferentially interact with calmodulin. In turn, targets can increase or decrease the calcium affinity of the calmodulin molecules to which they bind. Interestingly, experiments with the tryptic fragments showed that most targets have a much lower affinity for the N-lobe than for the C-lobe. Hence, the latter predominates in the formation of most calmodulin-target complexes. We showed that a relatively simple allosteric mechanism, based the classic MWC model, can capture the observed modulation of both the isolated C-lobe, and intact calmodulin, by individual targets. Moreover, our model can be naturally extended to study how the calcium affinity of a single pool of calmodulin is modulated by a mixture of competing targets in vivo.
doi:10.1371/journal.pcbi.1004063
PMCID: PMC4303274  PMID: 25611683
3.  Finding Our Way through Phenotypes 
Deans, Andrew R. | Lewis, Suzanna E. | Huala, Eva | Anzaldo, Salvatore S. | Ashburner, Michael | Balhoff, James P. | Blackburn, David C. | Blake, Judith A. | Burleigh, J. Gordon | Chanet, Bruno | Cooper, Laurel D. | Courtot, Mélanie | Csösz, Sándor | Cui, Hong | Dahdul, Wasila | Das, Sandip | Dececchi, T. Alexander | Dettai, Agnes | Diogo, Rui | Druzinsky, Robert E. | Dumontier, Michel | Franz, Nico M. | Friedrich, Frank | Gkoutos, George V. | Haendel, Melissa | Harmon, Luke J. | Hayamizu, Terry F. | He, Yongqun | Hines, Heather M. | Ibrahim, Nizar | Jackson, Laura M. | Jaiswal, Pankaj | James-Zorn, Christina | Köhler, Sebastian | Lecointre, Guillaume | Lapp, Hilmar | Lawrence, Carolyn J. | Le Novère, Nicolas | Lundberg, John G. | Macklin, James | Mast, Austin R. | Midford, Peter E. | Mikó, István | Mungall, Christopher J. | Oellrich, Anika | Osumi-Sutherland, David | Parkinson, Helen | Ramírez, Martín J. | Richter, Stefan | Robinson, Peter N. | Ruttenberg, Alan | Schulz, Katja S. | Segerdell, Erik | Seltmann, Katja C. | Sharkey, Michael J. | Smith, Aaron D. | Smith, Barry | Specht, Chelsea D. | Squires, R. Burke | Thacker, Robert W. | Thessen, Anne | Fernandez-Triana, Jose | Vihinen, Mauno | Vize, Peter D. | Vogt, Lars | Wall, Christine E. | Walls, Ramona L. | Westerfeld, Monte | Wharton, Robert A. | Wirkner, Christian S. | Woolley, James B. | Yoder, Matthew J. | Zorn, Aaron M. | Mabee, Paula
PLoS Biology  2015;13(1):e1002033.
Imagine if we could compute across phenotype data as easily as genomic data; this article calls for efforts to realize this vision and discusses the potential benefits.
Despite a large and multifaceted effort to understand the vast landscape of phenotypic data, their current form inhibits productive data analysis. The lack of a community-wide, consensus-based, human- and machine-interpretable language for describing phenotypes and their genomic and environmental contexts is perhaps the most pressing scientific bottleneck to integration across many key fields in biology, including genomics, systems biology, development, medicine, evolution, ecology, and systematics. Here we survey the current phenomics landscape, including data resources and handling, and the progress that has been made to accurately capture relevant data descriptions for phenotypes. We present an example of the kind of integration across domains that computable phenotypes would enable, and we call upon the broader biology community, publishers, and relevant funding agencies to support efforts to surmount today's data barriers and facilitate analytical reproducibility.
doi:10.1371/journal.pbio.1002033
PMCID: PMC4285398  PMID: 25562316
4.  COMBINE archive and OMEX format: one file to share all information to reproduce a modeling project 
BMC Bioinformatics  2014;15(1):369.
Background
With the ever increasing use of computational models in the biosciences, the need to share models and reproduce the results of published studies efficiently and easily is becoming more important. To this end, various standards have been proposed that can be used to describe models, simulations, data or other essential information in a consistent fashion. These constitute various separate components required to reproduce a given published scientific result.
Results
We describe the Open Modeling EXchange format (OMEX). Together with the use of other standard formats from the Computational Modeling in Biology Network (COMBINE), OMEX is the basis of the COMBINE Archive, a single file that supports the exchange of all the information necessary for a modeling and simulation experiment in biology. An OMEX file is a ZIP container that includes a manifest file, listing the content of the archive, an optional metadata file adding information about the archive and its content, and the files describing the model. The content of a COMBINE Archive consists of files encoded in COMBINE standards whenever possible, but may include additional files defined by an Internet Media Type. Several tools that support the COMBINE Archive are available, either as independent libraries or embedded in modeling software.
Conclusions
The COMBINE Archive facilitates the reproduction of modeling and simulation experiments in biology by embedding all the relevant information in one file. Having all the information stored and exchanged at once also helps in building activity logs and audit trails. We anticipate that the COMBINE Archive will become a significant help for modellers, as the domain moves to larger, more complex experiments such as multi-scale models of organs, digital organisms, and bioengineering.
Electronic supplementary material
The online version of this article (doi:10.1186/s12859-014-0369-z) contains supplementary material, which is available to authorized users.
doi:10.1186/s12859-014-0369-z
PMCID: PMC4272562  PMID: 25494900
Data format; Archive; Computational modeling; Reproducible research; Reproducible science
5.  A consensus yeast metabolic network reconstruction obtained from a community approach to systems biology 
Nature biotechnology  2008;26(10):1155-1160.
Genomic data now allow the large-scale manual or semi-automated reconstruction of metabolic networks. A network reconstruction represents a highly curated organism-specific knowledge base. A few genome-scale network reconstructions have appeared for metabolism in the baker’s yeast Saccharomyces cerevisiae. These alternative network reconstructions differ in scope and content, and further have used different terminologies to describe the same chemical entities, thus making comparisons between them difficult. The formulation of a ‘community consensus’ network that collects and formalizes the ‘community knowledge’ of yeast metabolism is thus highly desirable. We describe how we have produced a consensus metabolic network reconstruction for S. cerevisiae. Special emphasis is laid on referencing molecules to persistent databases or using database-independent forms such as SMILES or InChI strings, since this permits their chemical structure to be represented unambiguously and in a manner that permits automated reasoning. The reconstruction is readily available via a publicly accessible database and in the Systems Biology Markup Language, and we describe the manner in which it can be maintained as a community resource. It should serve as a common denominator for system biology studies of yeast. Similar strategies will be of benefit to communities studying genome-scale metabolic networks of other organisms.
doi:10.1038/nbt1492
PMCID: PMC4018421  PMID: 18846089
6.  Meeting report from the fourth meeting of the Computational Modeling in Biology Network (COMBINE) 
Standards in Genomic Sciences  2014;9(3):1285-1301.
The Computational Modeling in Biology Network (COMBINE) is an initiative to coordinate the development of community standards and formats in computational systems biology and related fields. This report summarizes the topics and activities of the fourth edition of the annual COMBINE meeting, held in Paris during September 16-20 2013, and attended by a total of 96 people. This edition pioneered a first day devoted to modeling approaches in biology, which attracted a broad audience of scientists thanks to a panel of renowned speakers. During subsequent days, discussions were held on many subjects including the introduction of new features in the various COMBINE standards, new software tools that use the standards, and outreach efforts. Significant emphasis went into work on extensions of the SBML format, and also into community-building. This year’s edition once again demonstrated that the COMBINE community is thriving, and still manages to help coordinate activities between different standards in computational systems biology.
doi:10.4056/sigs.5279417
PMCID: PMC4149000
7.  The EBI RDF platform: linked open data for the life sciences 
Bioinformatics  2014;30(9):1338-1339.
Motivation: Resource description framework (RDF) is an emerging technology for describing, publishing and linking life science data. As a major provider of bioinformatics data and services, the European Bioinformatics Institute (EBI) is committed to making data readily accessible to the community in ways that meet existing demand. The EBI RDF platform has been developed to meet an increasing demand to coordinate RDF activities across the institute and provides a new entry point to querying and exploring integrated resources available at the EBI.
Availability: http://www.ebi.ac.uk/rdf
Contact: jupp@ebi.ac.uk
doi:10.1093/bioinformatics/btt765
PMCID: PMC3998127  PMID: 24413672
8.  SBML qualitative models: a model representation format and infrastructure to foster interactions between qualitative modelling formalisms and tools 
BMC Systems Biology  2013;7:135.
Background
Qualitative frameworks, especially those based on the logical discrete formalism, are increasingly used to model regulatory and signalling networks. A major advantage of these frameworks is that they do not require precise quantitative data, and that they are well-suited for studies of large networks. While numerous groups have developed specific computational tools that provide original methods to analyse qualitative models, a standard format to exchange qualitative models has been missing.
Results
We present the Systems Biology Markup Language (SBML) Qualitative Models Package (“qual”), an extension of the SBML Level 3 standard designed for computer representation of qualitative models of biological networks. We demonstrate the interoperability of models via SBML qual through the analysis of a specific signalling network by three independent software tools. Furthermore, the collective effort to define the SBML qual format paved the way for the development of LogicalModel, an open-source model library, which will facilitate the adoption of the format as well as the collaborative development of algorithms to analyse qualitative models.
Conclusions
SBML qual allows the exchange of qualitative models among a number of complementary software tools. SBML qual has the potential to promote collaborative work on the development of novel computational approaches, as well as on the specification and the analysis of comprehensive qualitative models of regulatory and signalling networks.
doi:10.1186/1752-0509-7-135
PMCID: PMC3892043  PMID: 24321545
9.  A community-driven global reconstruction of human metabolism 
Nature biotechnology  2013;31(5):10.1038/nbt.2488.
Multiple models of human metabolism have been reconstructed, but each represents only a subset of our knowledge. Here we describe Recon 2, a community-driven, consensus ‘metabolic reconstruction’, which is the most comprehensive representation of human metabolism that is applicable to computational modeling. Compared with its predecessors, the reconstruction has improved topological and functional features, including ~2× more reactions and ~1.7× more unique metabolites. Using Recon 2 we predicted changes in metabolite biomarkers for 49 inborn errors of metabolism with 77% accuracy when compared to experimental data. Mapping metabolomic data and drug information onto Recon 2 demonstrates its potential for integrating and analyzing diverse data types. Using protein expression data, we automatically generated a compendium of 65 cell type–specific models, providing a basis for manual curation or investigation of cell-specific metabolic properties. Recon 2 will facilitate many future biomedical studies and is freely available at http://humanmetabolism.org/.
doi:10.1038/nbt.2488
PMCID: PMC3856361  PMID: 23455439
10.  Path2Models: large-scale generation of computational models from biochemical pathway maps 
BMC Systems Biology  2013;7:116.
Background
Systems biology projects and omics technologies have led to a growing number of biochemical pathway models and reconstructions. However, the majority of these models are still created de novo, based on literature mining and the manual processing of pathway data.
Results
To increase the efficiency of model creation, the Path2Models project has automatically generated mathematical models from pathway representations using a suite of freely available software. Data sources include KEGG, BioCarta, MetaCyc and SABIO-RK. Depending on the source data, three types of models are provided: kinetic, logical and constraint-based. Models from over 2 600 organisms are encoded consistently in SBML, and are made freely available through BioModels Database at http://www.ebi.ac.uk/biomodels-main/path2models. Each model contains the list of participants, their interactions, the relevant mathematical constructs, and initial parameter values. Most models are also available as easy-to-understand graphical SBGN maps.
Conclusions
To date, the project has resulted in more than 140 000 freely available models. Such a resource can tremendously accelerate the development of mathematical models by providing initial starting models for simulation and analysis, which can be subsequently curated and further parameterized.
doi:10.1186/1752-0509-7-116
PMCID: PMC4228421  PMID: 24180668
Modular rate law; Constraint based models; Logical models; SBGN; SBML
11.  Integration of Biochemical and Electrical Signaling-Multiscale Model of the Medium Spiny Neuron of the Striatum 
PLoS ONE  2013;8(7):e66811.
Neuron behavior results from the interplay between networks of biochemical processes and electrical signaling. Synaptic plasticity is one of the neuronal properties emerging from such an interaction. One of the current approaches to study plasticity is to model either its electrical aspects or its biochemical components. Among the chief reasons are the different time scales involved, electrical events happening in milliseconds while biochemical cascades respond in minutes or hours. In order to create multiscale models taking in consideration both aspects simultaneously, one needs to synchronize the two models, and exchange relevant variable values. We present a new event-driven algorithm to synchronize different neuronal models, which decreases computational time and avoids superfluous synchronizations. The algorithm is implemented in the TimeScales framework. We demonstrate its use by simulating a new multiscale model of the Medium Spiny Neuron of the Neostriatum. The model comprises over a thousand dendritic spines, where the electrical model interacts with the respective instances of a biochemical model. Our results show that a multiscale model is able to exhibit changes of synaptic plasticity as a result of the interaction between electrical and biochemical signaling. Our synchronization strategy is general enough to be used in simulations of other models with similar synchronization issues, such as networks of neurons. Moreover, the integration between the electrical and the biochemical models opens up the possibility to investigate multiscale process, like synaptic plasticity, in a more global manner, while taking into account a more realistic description of the underlying mechanisms.
doi:10.1371/journal.pone.0066811
PMCID: PMC3700997  PMID: 23843966
12.  Cooperative Binding 
PLoS Computational Biology  2013;9(6):e1003106.
Molecular binding is an interaction between molecules that results in a stable association between those molecules. Cooperative binding occurs if the number of binding sites of a macromolecule that are occupied by a specific type of ligand is a nonlinear function of this ligand's concentration. This can be due, for instance, to an affinity for the ligand that depends on the amount of ligand bound. Cooperativity can be positive (supralinear) or negative (infralinear). Cooperative binding is most often observed in proteins, but nucleic acids can also exhibit cooperative binding, for instance of transcription factors. Cooperative binding has been shown to be the mechanism underlying a large range of biochemical and physiological processes.
doi:10.1371/journal.pcbi.1003106
PMCID: PMC3699289  PMID: 23843752
13.  Towards the Collaborative Curation of the Registry underlying identifiers.org 
The MIRIAM Registry (http://www.ebi.ac.uk/miriam/) records information about collections of data in the life sciences, as well as where it can be obtained. This information is used, in combination with the resolving infrastructure of Identifiers.org (http://identifiers.org/), to generate globally unique identifiers, in the form of Uniform Resource Identifier. These identifiers are now widely used to provide perennial cross-references and annotations. The growing demand for these identifiers results in a significant increase in curational efforts to maintain the underlying registry. This requires the design and implementation of an economically viable and sustainable solution able to cope with such expansion. We briefly describe the Registry, the current curation duties entailed, and our plans to extend and distribute this workload through collaborative and community efforts.
doi:10.1093/database/bat017
PMCID: PMC3625955  PMID: 23584831
14.  LibKiSAO: a Java library for Querying KiSAO 
BMC Research Notes  2012;5:520.
Background
The Kinetic Simulation Algorithm Ontology (KiSAO) supplies information about existing algorithms available for the simulation of Systems Biology models, their characteristics, parameters and inter-relationships. KiSAO enables the unambiguous identification of algorithms from simulation descriptions. Information about analogous methods having similar characteristics and about algorithm parameters incorporated into KiSAO is desirable for simulation tools. To retrieve this information programmatically an application programming interface (API) for KiSAO is needed.
Findings
We developed libKiSAO, a Java library to enable querying of the KiSA Ontology. It implements methods to retrieve information about simulation algorithms stored in KiSAO, their characteristics and parameters, and methods to query the algorithm hierarchy and search for similar algorithms providing comparable results for the same simulation set-up. Using libKiSAO, simulation tools can make logical inferences based on this knowledge and choose the most appropriate algorithm to perform a simulation. LibKiSAO also enables simulation tools to handle a wider range of simulation descriptions by determining which of the available methods are similar and can be used instead of the one indicated in the simulation description if that one is not implemented.
Conclusions
LibKiSAO enables Java applications to easily access information about simulation algorithms, their characteristics and parameters stored in the OWL-encoded Kinetic Simulation Algorithm Ontology. LibKiSAO can be used by simulation description editors and simulation tools to improve reproducibility of computational simulation tasks and facilitate model re-use.
doi:10.1186/1756-0500-5-520
PMCID: PMC3532180  PMID: 23006857
Java library; Simulation; Algorithm search; Ontology
15.  Calcium Input Frequency, Duration and Amplitude Differentially Modulate the Relative Activation of Calcineurin and CaMKII 
PLoS ONE  2012;7(9):e43810.
NMDA receptor dependent long-term potentiation (LTP) and long-term depression (LTD) are two prominent forms of synaptic plasticity, both of which are triggered by post-synaptic calcium elevation. To understand how calcium selectively stimulates two opposing processes, we developed a detailed computational model and performed simulations with different calcium input frequencies, amplitudes, and durations. We show that with a total amount of calcium ions kept constant, high frequencies of calcium pulses stimulate calmodulin more efficiently. Calcium input activates both calcineurin and Ca2+/calmodulin-dependent protein kinase II (CaMKII) at all frequencies, but increased frequencies shift the relative activation from calcineurin to CaMKII. Irrespective of amplitude and duration of the inputs, the total amount of calcium ions injected adjusts the sensitivity of the system to calcium input frequencies. At a given frequency, the quantity of CaMKII activated is proportional to the total amount of calcium. Thus, an input of a small amount of calcium at high frequencies can induce the same activation of CaMKII as a larger amount, at lower frequencies. Finally, the extent of activation of CaMKII signals with high calcium frequency is further controlled by other factors, including the availability of calmodulin, and by the potency of phosphatase inhibitors.
doi:10.1371/journal.pone.0043810
PMCID: PMC3433481  PMID: 22962589
16.  Qualitative translation of relations from BioPAX to SBML qual 
Bioinformatics  2012;28(20):2648-2653.
Motivation: The biological pathway exchange language (BioPAX) and the systems biology markup language (SBML) belong to the most popular modeling and data exchange languages in systems biology. The focus of SBML is quantitative modeling and dynamic simulation of models, whereas the BioPAX specification concentrates mainly on visualization and qualitative analysis of pathway maps. BioPAX describes reactions and relations. In contrast, SBML core exclusively describes quantitative processes such as reactions. With the SBML qualitative models extension (qual), it has recently also become possible to describe relations in SBML. Before the development of SBML qual, relations could not be properly translated into SBML. Until now, there exists no BioPAX to SBML converter that is fully capable of translating both reactions and relations.
Results: The entire nature pathway interaction database has been converted from BioPAX (Level 2 and Level 3) into SBML (Level 3 Version 1) including both reactions and relations by using the new qual extension package. Additionally, we present the new webtool BioPAX2SBML for further BioPAX to SBML conversions. Compared with previous conversion tools, BioPAX2SBML is more comprehensive, more robust and more exact.
Availability: BioPAX2SBML is freely available at http://webservices.cs.uni-tuebingen.de/ and the complete collection of the PID models is available at http://www.cogsys.cs.uni-tuebingen.de/downloads/Qualitative-Models/.
Contact: finja.buechel@uni-tuebingen.de
Supplementary Information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/bts508
PMCID: PMC3467751  PMID: 22923304
17.  Software support for SBGN maps: SBGN-ML and LibSBGN 
Bioinformatics  2012;28(15):2016-2021.
Motivation: LibSBGN is a software library for reading, writing and manipulating Systems Biology Graphical Notation (SBGN) maps stored using the recently developed SBGN-ML file format. The library (available in C++ and Java) makes it easy for developers to add SBGN support to their tools, whereas the file format facilitates the exchange of maps between compatible software applications. The library also supports validation of maps, which simplifies the task of ensuring compliance with the detailed SBGN specifications. With this effort we hope to increase the adoption of SBGN in bioinformatics tools, ultimately enabling more researchers to visualize biological knowledge in a precise and unambiguous manner.
Availability and implementation: Milestone 2 was released in December 2011. Source code, example files and binaries are freely available under the terms of either the LGPL v2.1+ or Apache v2.0 open source licenses from http://libsbgn.sourceforge.net.
Contact: sbgn-libsbgn@lists.sourceforge.net
doi:10.1093/bioinformatics/bts270
PMCID: PMC3400951  PMID: 22581176
18.  Structural Analysis and Stochastic Modelling Suggest a Mechanism for Calmodulin Trapping by CaMKII 
PLoS ONE  2012;7(1):e29406.
Activation of CaMKII by calmodulin and the subsequent maintenance of constitutive activity through autophosphorylation at threonine residue 286 (Thr286) are thought to play a major role in synaptic plasticity. One of the effects of autophosphorylation at Thr286 is to increase the apparent affinity of CaMKII for calmodulin, a phenomenon known as “calmodulin trapping”. It has previously been suggested that two binding sites for calmodulin exist on CaMKII, with high and low affinities, respectively. We built structural models of calmodulin bound to both of these sites. Molecular dynamics simulation showed that while binding of calmodulin to the supposed low-affinity binding site on CaMKII is compatible with closing (and hence, inactivation) of the kinase, and could even favour it, binding to the high-affinity site is not. Stochastic simulations of a biochemical model showed that the existence of two such binding sites, one of them accessible only in the active, open conformation, would be sufficient to explain calmodulin trapping by CaMKII. We can explain the effect of CaMKII autophosphorylation at Thr286 on calmodulin trapping: It stabilises the active state and therefore makes the high-affinity binding site accessible. Crucially, a model with only one binding site where calmodulin binding and CaMKII inactivation are strictly mutually exclusive cannot reproduce calmodulin trapping. One of the predictions of our study is that calmodulin binding in itself is not sufficient for CaMKII activation, although high-affinity binding of calmodulin is.
doi:10.1371/journal.pone.0029406
PMCID: PMC3261145  PMID: 22279535
19.  Neuronvisio: A Graphical User Interface with 3D Capabilities for NEURON 
The NEURON simulation environment is a commonly used tool to perform electrical simulation of neurons and neuronal networks. The NEURON User Interface, based on the now discontinued InterViews library, provides some limited facilities to explore models and to plot their simulation results. Other limitations include the inability to generate a three-dimensional visualization, no standard mean to save the results of simulations, or to store the model geometry within the results. Neuronvisio (http://neuronvisio.org) aims to address these deficiencies through a set of well designed python APIs and provides an improved UI, allowing users to explore and interact with the model. Neuronvisio also facilitates access to previously published models, allowing users to browse, download, and locally run NEURON models stored in ModelDB. Neuronvisio uses the matplotlib library to plot simulation results and uses the HDF standard format to store simulation results. Neuronvisio can be viewed as an extension of NEURON, facilitating typical user workflows such as model browsing, selection, download, compilation, and simulation. The 3D viewer simplifies the exploration of complex model structure, while matplotlib permits the plotting of high-quality graphs. The newly introduced ability of saving numerical results allows users to perform additional analysis on their previous simulations.
doi:10.3389/fninf.2012.00020
PMCID: PMC3368231  PMID: 22685429
neuron model; 3D visualization; electrophysiological model; hdf storage; matplotlib integration
20.  Reproducible computational biology experiments with SED-ML - The Simulation Experiment Description Markup Language 
BMC Systems Biology  2011;5:198.
Background
The increasing use of computational simulation experiments to inform modern biological research creates new challenges to annotate, archive, share and reproduce such experiments. The recently published Minimum Information About a Simulation Experiment (MIASE) proposes a minimal set of information that should be provided to allow the reproduction of simulation experiments among users and software tools.
Results
In this article, we present the Simulation Experiment Description Markup Language (SED-ML). SED-ML encodes in a computer-readable exchange format the information required by MIASE to enable reproduction of simulation experiments. It has been developed as a community project and it is defined in a detailed technical specification and additionally provides an XML schema. The version of SED-ML described in this publication is Level 1 Version 1. It covers the description of the most frequent type of simulation experiments in the area, namely time course simulations. SED-ML documents specify which models to use in an experiment, modifications to apply on the models before using them, which simulation procedures to run on each model, what analysis results to output, and how the results should be presented. These descriptions are independent of the underlying model implementation. SED-ML is a software-independent format for encoding the description of simulation experiments; it is not specific to particular simulation tools. Here, we demonstrate that with the growing software support for SED-ML we can effectively exchange executable simulation descriptions.
Conclusions
With SED-ML, software can exchange simulation experiment descriptions, enabling the validation and reuse of simulation experiments in different tools. Authors of papers reporting simulation experiments can make their simulation protocols available for other scientists to reproduce the results. Because SED-ML is agnostic about exact modeling language(s) used, experiments covering models from different fields of research can be accurately described and combined.
doi:10.1186/1752-0509-5-198
PMCID: PMC3292844  PMID: 22172142
21.  Identifiers.org and MIRIAM Registry: community resources to provide persistent identification 
Nucleic Acids Research  2011;40(Database issue):D580-D586.
The Minimum Information Required in the Annotation of Models Registry (http://www.ebi.ac.uk/miriam) provides unique, perennial and location-independent identifiers for data used in the biomedical domain. At its core is a shared catalogue of data collections, for each of which an individual namespace is created, and extensive metadata recorded. This namespace allows the generation of Uniform Resource Identifiers (URIs) to uniquely identify any record in a collection. Moreover, various services are provided to facilitate the creation and resolution of the identifiers. Since its launch in 2005, the system has evolved in terms of the structure of the identifiers provided, the software infrastructure, the number of data collections recorded, as well as the scope of the Registry itself. We describe here the new parallel identification scheme and the updated supporting software infrastructure. We also introduce the new Identifiers.org service (http://identifiers.org) that is built upon the information stored in the Registry and which provides directly resolvable identifiers, in the form of Uniform Resource Locators (URLs). The flexibility of the identification scheme and resolving system allows its use in many different fields, where unambiguous and perennial identification of data entities are necessary.
doi:10.1093/nar/gkr1097
PMCID: PMC3245029  PMID: 22140103
22.  Meeting report from the first meetings of the Computational Modeling in Biology Network (COMBINE) 
Standards in Genomic Sciences  2011;5(2):230-242.
The Computational Modeling in Biology Network (COMBINE), is an initiative to coordinate the development of the various community standards and formats in computational systems biology and related fields. This report summarizes the activities pursued at the first annual COMBINE meeting held in Edinburgh on October 6-9 2010 and the first HARMONY hackathon, held in New York on April 18-22 2011. The first of those meetings hosted 81 attendees. Discussions covered both official COMBINE standards-(BioPAX, SBGN and SBML), as well as emerging efforts and interoperability between different formats. The second meeting, oriented towards software developers, welcomed 59 participants and witnessed many technical discussions, development of improved standards support in community software systems and conversion between the standards. Both meetings were resounding successes and showed that the field is now mature enough to develop representation formats and related standards in a coordinated manner.
doi:10.4056/sigs.2034671
PMCID: PMC3235518  PMID: 22180826
23.  Controlled vocabularies and semantics in systems biology 
The use of computational modeling to describe and analyze biological systems is at the heart of systems biology. This Perspective discusses the development and use of ontologies that are designed to add semantic information to computational models and simulations.
The use of computational modeling to describe and analyze biological systems is at the heart of systems biology. Model structures, simulation descriptions and numerical results can be encoded in structured formats, but there is an increasing need to provide an additional semantic layer. Semantic information adds meaning to components of structured descriptions to help identify and interpret them unambiguously. Ontologies are one of the tools frequently used for this purpose. We describe here three ontologies created specifically to address the needs of the systems biology community. The Systems Biology Ontology (SBO) provides semantic information about the model components. The Kinetic Simulation Algorithm Ontology (KiSAO) supplies information about existing algorithms available for the simulation of systems biology models, their characterization and interrelationships. The Terminology for the Description of Dynamics (TEDDY) categorizes dynamical features of the simulation results and general systems behavior. The provision of semantic information extends a model's longevity and facilitates its reuse. It provides useful insight into the biology of modeled processes, and may be used to make informed decisions on subsequent simulation experiments.
doi:10.1038/msb.2011.77
PMCID: PMC3261705  PMID: 22027554
dynamics; kinetics; model; ontology; simulation
24.  Retrieval, alignment, and clustering of computational models based on semantic annotations 
As the number of computational systems biology models increases, new methods are needed to explore their content and build connections with experimental data. In this Perspective article, the authors propose a flexible semantic framework that can help achieve these aims.
The exploding number of computational models produced by Systems Biologists over the last years is an invitation to structure and exploit this new wealth of information. Researchers would like to trace models relevant to specific scientific questions, to explore their biological content, to align and combine them, and to match them with experimental data. To automate these processes, it is essential to consider semantic annotations, which describe their biological meaning. As a prerequisite for a wide range of computational methods, we propose general and flexible similarity measures for Systems Biology models computed from semantic annotations. By using these measures and a large extensible ontology, we implement a platform that can retrieve, cluster, and align Systems Biology models and experimental data sets. At present, its major application is the search for relevant models in the BioModels Database, starting from initial models, data sets, or lists of biological concepts. Beyond similarity searches, the representation of models by semantic feature vectors may pave the way for visualisation, exploration, and statistical analysis of large collections of models and corresponding data.
doi:10.1038/msb.2011.41
PMCID: PMC3159965  PMID: 21772260
BioModels database; ontology; semanticSBML; similarity measure
25.  JSBML: a flexible Java library for working with SBML 
Bioinformatics  2011;27(15):2167-2168.
Summary: The specifications of the Systems Biology Markup Language (SBML) define standards for storing and exchanging computer models of biological processes in text files. In order to perform model simulations, graphical visualizations and other software manipulations, an in-memory representation of SBML is required. We developed JSBML for this purpose. In contrast to prior implementations of SBML APIs, JSBML has been designed from the ground up for the Java™ programming language, and can therefore be used on all platforms supported by a Java Runtime Environment. This offers important benefits for Java users, including the ability to distribute software as Java Web Start applications. JSBML supports all SBML Levels and Versions through Level 3 Version 1, and we have strived to maintain the highest possible degree of compatibility with the popular library libSBML. JSBML also supports modules that can facilitate the development of plugins for end user applications, as well as ease migration from a libSBML-based backend.
Availability: Source code, binaries and documentation for JSBML can be freely obtained under the terms of the LGPL 2.1 from the website http://sbml.org/Software/JSBML.
Contact: jsbml-team@sbml.org
Supplementary information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/btr361
PMCID: PMC3137227  PMID: 21697129

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