Calmodulin sits at the center of molecular mechanisms underlying learning and memory. Its complex and sometimes opposite influences, mediated via the binding to various proteins, are yet to be fully understood. Calcium/calmodulin-dependent protein kinase II (CaMKII) and calcineurin (CaN) both bind open calmodulin, favoring Long-Term Potentiation (LTP) or Depression (LTD) respectively. Neurogranin binds to the closed conformation of calmodulin and its impact on synaptic plasticity is less clear. We set up a mechanistic computational model based on allosteric principles to simulate calmodulin state transitions and its interactions with calcium ions and the three binding partners mentioned above. We simulated calcium spikes at various frequencies and show that neurogranin regulates synaptic plasticity along three modalities. At low spike frequencies, neurogranin inhibits the onset of LTD by limiting CaN activation. At intermediate frequencies, neurogranin facilitates LTD, but limits LTP by precluding binding of CaMKII with calmodulin. Finally, at high spike frequencies, neurogranin promotes LTP by enhancing CaMKII autophosphorylation. While neurogranin might act as a calmodulin buffer, it does not significantly preclude the calmodulin opening by calcium. On the contrary, neurogranin synchronizes the opening of calmodulin's two lobes and promotes their activation at specific frequencies. Neurogranin suppresses basal CaN activity, thus increasing the chance of CaMKII trans-autophosphorylation at high-frequency calcium spikes. Taken together, our study reveals dynamic regulatory roles played by neurogranin on synaptic plasticity, which provide mechanistic explanations for opposing experimental findings.

The Disease Maps Project builds on a network of scientific and clinical groups that exchange best practices, share information and develop systems biomedicine tools. The project aims for an integrated, highly curated and user-friendly platform for disease-related knowledge. The primary focus of disease maps is on interconnected signaling, metabolic and gene regulatory network pathways represented in standard formats. The involvement of domain experts ensures that the key disease hallmarks are covered and relevant, up-to-date knowledge is adequately represented. Expert-curated and computer readable, disease maps may serve as a compendium of knowledge, allow for data-supported hypothesis generation or serve as a scaffold for the generation of predictive mathematical models. This article summarizes the 2nd Disease Maps Community meeting, highlighting its important topics and outcomes. We outline milestones on the roadmap for the future development of disease maps, including creating and maintaining standardized disease maps; sharing parts of maps that encode common human disease mechanisms; providing technical solutions for complexity management of maps; and Web tools for in-depth exploration of such maps. A dedicated discussion was focused on mathematical modeling approaches, as one of the main goals of disease map development is the generation of mathematically interpretable representations to predict disease comorbidity or drug response and to suggest drug repositioning, altogether supporting clinical decisions.

Quick tips for creating effective and impactful biological pathways using the Systems Biology Graphical Notation

BACKGROUND: Interoperability between formats is a recurring problem in systems biology research. Many tools have been developed to convert computational models from one format to another. However, they have been developed independently, resulting in redundancy of efforts and lack of synergy. RESULTS: Here we present the System Biology Format Converter (SBFC), which provide a generic framework to potentially convert any format into another. The framework currently includes several converters translating between the following formats: SBML, BioPAX, SBGN-ML, Matlab, Octave, XPP, GPML, Dot, MDL and APM. This software is written in Java and can be used as a standalone executable or web service. CONCLUSIONS: The SBFC framework is an evolving software project. Existing converters can be used and improved, and new converters can be easily added, making SBFC useful to both modellers and developers. The source code and documentation of the framework are freely available from the project web site.

UNLABELLED: JSBML, the official pure Java programming library for the Systems Biology Markup Language (SBML) format, has evolved with the advent of different modeling formalisms in systems biology and their ability to be exchanged and represented via extensions of SBML. JSBML has matured into a major, active open-source project with contributions from a growing, international team of developers who not only maintain compatibility with SBML, but also drive steady improvements to the Java interface and promote ease-of-use with end users. AVAILABILITY AND IMPLEMENTATION: 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. More information about JSBML can be found in the user guide at http://sbml.org/Software/JSBML/docs/. CONTACT: [email protected] or [email protected] SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

MOTIVATION: On the semantic web, in life sciences in particular, data is often distributed via multiple resources. Each of these sources is likely to use their own International Resource Identifier for conceptually the same resource or database record. The lack of correspondence between identifiers introduces a barrier when executing federated SPARQL queries across life science data. RESULTS: We introduce a novel SPARQL-based service to enable on-the-fly integration of life science data. This service uses the identifier patterns defined in the Identifiers.org Registry to generate a plurality of identifier variants, which can then be used to match source identifiers with target identifiers. We demonstrate the utility of this identifier integration approach by answering queries across major producers of life science Linked Data. AVAILABILITY AND IMPLEMENTATION: The SPARQL-based identifier conversion service is available without restriction at http://identifiers.org/services/sparql.

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.

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.

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.

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.

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/.

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: [email protected].

BACKGROUND: Computing accurate nucleic acid melting temperatures has become a crucial step for the efficiency and the optimisation of numerous molecular biology techniques such as in situ hybridization, PCR, antigene targeting, and microarrays. MELTING is a free open source software which computes the enthalpy, entropy and melting temperature of nucleic acids. MELTING 4.2 was able to handle several types of hybridization such as DNA/DNA, RNA/RNA, DNA/RNA and provided corrections to melting temperatures due to the presence of sodium. The program can use either an approximative approach or a more accurate Nearest-Neighbor approach. RESULTS: Two new versions of the MELTING software have been released. MELTING 4.3 is a direct update of version 4.2, integrating newly available thermodynamic parameters for inosine, a modified adenine base with an universal base capacity, and incorporates a correction for magnesium. MELTING 5 is a complete reimplementation which allows much greater flexibility and extensibility. It incorporates all the thermodynamic parameters and corrections provided in MELTING 4.x and introduces a large set of thermodynamic formulae and parameters, to facilitate the calculation of melting temperatures for perfectly matching sequences, mismatches, bulge loops, CNG repeats, dangling ends, inosines, locked nucleic acids, 2-hydroxyadenines and azobenzenes. It also includes temperature corrections for monovalent ions (sodium, potassium, Tris), magnesium ions and commonly used denaturing agents such as formamide and DMSO. CONCLUSIONS: MELTING is a useful and very flexible tool for predicting melting temperatures using approximative formulae or Nearest-Neighbor approaches, where one can select different sets of Nearest-Neighbor parameters, corrections and formulae. Both versions are freely available at http://sourceforge.net/projects/melting/and at http://www.ebi.ac.uk/compneur-srv/melting/under the terms of the GPL license.

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.

This FAIRsharing record describes: The MIASE Guidelines, initiated by the BioModels.net effort, are a community effort to identify the Minimal Information About a Simulation Experiment, necessary to enable the reproducible simulation experiments. Consequently, the MIASE Guidelines list the information that a modeller needs to provide to enable the execution and reproduction of a numerical simulation experiment, derived from a given set of quantitative models. MIASE is a set of guidelines suitable for use with any structured format for simulation experiments. As such, MIASE is designed to help modelers and software tools to exchange their simulation settings and to foster collaboration.

Exchanging and sharing scientific results are essential for researchers in the field of computational modelling. BioModels.net defines agreed-upon standards for model curation. A fundamental one, MIRIAM (Minimum Information Requested in the Annotation of Models), standardises the annotation and curation process of quantitative models in biology. To support this standard, MIRIAM Resources maintains a set of standard data types for annotating models, and provides services for manipulating these annotations. Furthermore, BioModels.net creates controlled vocabularies, such as SBO (Systems Biology Ontology) which strictly indexes, defines and links terms used in Systems Biology. Finally, BioModels Database provides a free, centralised, publicly accessible database for storing, searching and retrieving curated and annotated computational models. Each resource provides a web interface to submit, search, retrieve and display its data. In addition, the BioModels.net team provides a set of Web Services which allows the community to programmatically access the resources. A user is then able to perform remote queries, such as retrieving a model and resolving all its MIRIAM Annotations, as well as getting the details about the associated SBO terms. These web services use established standards. Communications rely on SOAP (Simple Object Access Protocol) messages and the available queries are described in a WSDL (Web Services Description Language) file. Several libraries are provided in order to simplify the development of client software. BioModels.net Web Services make one step further for the researchers to simulate and understand the entirety of a biological system, by allowing them to retrieve biological models in their own tool, combine queries in workflows and efficiently analyse models.

BACKGROUND: The study of biological systems demands computational support. If targeting a biological problem, the reuse of existing computational models can save time and effort. Deciding for potentially suitable models, however, becomes more challenging with the increasing number of computational models available, and even more when considering the models' growing complexity. Firstly, among a set of potential model candidates it is difficult to decide for the model that best suits ones needs. Secondly, it is hard to grasp the nature of an unknown model listed in a search result set, and to judge how well it fits for the particular problem one has in mind. RESULTS: Here we present an improved search approach for computational models of biological processes. It is based on existing retrieval and ranking methods from Information Retrieval. The approach incorporates annotations suggested by MIRIAM, and additional meta-information. It is now part of the search engine of BioModels Database, a standard repository for computational models. CONCLUSIONS: The introduced concept and implementation are, to our knowledge, the first application of Information Retrieval techniques on model search in Computational Systems Biology. Using the example of BioModels Database, it was shown that the approach is feasible and extends the current possibilities to search for relevant models. The advantages of our system over existing solutions are that we incorporate a rich set of meta-information, and that we provide the user with a relevance ranking of the models found for a query. Better search capabilities in model databases are expected to have a positive effect on the reuse of existing models.

BACKGROUND: The need to build a tool to facilitate the quick creation and editing of models encoded in the Systems Biology Markup language (SBML) has been growing with the number of users and the increased complexity of the language. SBMLeditor tries to answer this need by providing a very simple, low level editor of SBML files. Users can create and remove all the necessary bits and pieces of SBML in a controlled way, that maintains the validity of the final SBML file. RESULTS: SBMLeditor is written in JAVA using JCompneur, a library providing interfaces to easily display an XML document as a tree. This decreases dramatically the development time for a new XML editor. The possibility to include custom dialogs for different tags allows a lot of freedom for the editing and validation of the document. In addition to Xerces, SBMLeditor uses libSBML to check the validity and consistency of SBML files. A graphical equation editor allows an easy manipulation of MathML. SBMLeditor can be used as a module of the Systems Biology Workbench. CONCLUSION: SBMLeditor contains many improvements compared to a generic XML editor, and allow users to create an SBML model quickly and without syntactic errors.

UNLABELLED: CellML and SBML are XML-based languages for storage and exchange of molecular biological and physiological reaction models. They use very similar subsets of MathML to specify the mathematical aspects of the models. CellML2SBML is implemented as a suite of XSLT stylesheets that, when applied consecutively, convert models expressed in CellML into SBML without significant loss of information. The converter is based on the most recent stable versions of the languages (CellML version 1.1; SBML Level 2 Version 1), and the XSLT used in the stylesheets adheres to the XSLT version 1.0 specification. Of all 306 models in the CellML repository in April 2005, CellML2SBML converted 91% automatically into SBML. Minor manual changes to the unit definitions in the originals raised the percentage of successful conversions to 96%. AVAILABILITY: http://sbml.org/software/cellml2sbml/. SUPPLEMENTARY INFORMATION: Instructions for use and further documentation available on http://sbml.org/software/cellml2sbml/

Integration of neurotransmitter and neuromodulator signals in the striatum plays a central role in the functions and dysfunctions of the basal ganglia. DARPP-32 is a key actor of this integration in the GABAergic medium-size spiny neurons, in particular in response to dopamine and glutamate. When phosphorylated by cAMP-dependent protein kinase (PKA), DARPP-32 inhibits protein phosphatase-1 (PP1), whereas when phosphorylated by cyclin-dependent kinase 5 (CDK5) it inhibits PKA. DARPP-32 is also regulated by casein kinases and by several protein phosphatases. These complex and intricate regulations make simple predictions of DARPP-32 dynamic behaviour virtually impossible. We used detailed quantitative modelling of the regulation of DARPP-32 phosphorylation to improve our understanding of its function. The models included all the combinations of the three best-characterized phosphorylation sites of DARPP-32, their regulation by kinases and phosphatases, and the regulation of those enzymes by cAMP and Ca(2+) signals. Dynamic simulations allowed us to observe the temporal relationships between cAMP and Ca(2+) signals. We confirmed that the proposed regulation of protein phosphatase-2A (PP2A) by calcium can account for the observed decrease of Threonine 75 phosphorylation upon glutamate receptor activation. DARPP-32 is not simply a switch between PP1-inhibiting and PKA-inhibiting states. Sensitivity analysis showed that CDK5 activity is a major regulator of the response, as previously suggested. Conversely, the strength of the regulation of PP2A by PKA or by calcium had little effect on the PP1-inhibiting function of DARPP-32 in these conditions. The simulations showed that DARPP-32 is not only a robust signal integrator, but that its response also depends on the delay between cAMP and calcium signals affecting the response to the latter. This integration did not depend on the concentration of DARPP-32, while the absolute effect on PP1 varied linearly. In silico mutants showed that Ser137 phosphorylation affects the influence of the delay between dopamine and glutamate, and that constitutive phosphorylation in Ser137 transforms DARPP-32 in a quasi-irreversible switch. This work is a first attempt to better understand the complex interactions between cAMP and Ca(2+) regulation of DARPP-32. Progressive inclusion of additional components should lead to a realistic model of signalling networks underlying the function of striatal neurons.

BACKGROUND: DopaNet http://www.dopanet.org is a Systems Biology initiative that aims to investigate precisely and quantitatively all the aspects of neurotransmission in a specific neuronal system, the mesotelencephalic dopamine system. The project should lead to large-scale models of molecular and cellular processes involved in neuronal signaling. A prerequisite is the proper storage of knowledge coming from the literature. METHODS: DopaNet Molecular Pages are highly structured descriptions of quantitative parameters related to a specific molecular complex involved in neuronal signal processing. A Molecular Page is built by maintainers who are experts in the field, and responsible for the quality of the page content. Each piece of data is identified by a specific ontology code, annotated (method of acquisition, species, etc.) and linked to the relevant bibliography. The Molecular Pages are stored as XML files, and processed through the DopaNet Web Service, which provides functionalities to edit the Molecular Pages, to cross-link the Pages and generate the public display, and to search them. CONCLUSIONS: DopaNet Molecular Pages are one of the core resources of the DopaNet project but should be of widespread utility in the field of Systems Neurobiology.

MOTIVATION: Molecular biotechnology now makes it possible to build elaborate systems models, but the systems biology community needs information standards if models are to be shared, evaluated and developed cooperatively. RESULTS: We summarize the Systems Biology Markup Language (SBML) Level 1, a free, open, XML-based format for representing biochemical reaction networks. SBML is a software-independent language for describing models common to research in many areas of computational biology, including cell signaling pathways, metabolic pathways, gene regulation, and others. AVAILABILITY: The specification of SBML Level 1 is freely available from http://www.sbml.org/

UNLABELLED: MELTING computes the enthalpy and entropy of an oligonucleotide duplex helix-coil transition, and then its melting temperature. The program uses the method of nearest-neighbours. The set of thermodynamic parameters can be easily customized. The program provides several correction methods for the concentration of salt. MELTING is a free program, available at no cost and open-source. Perl scripts are provided to show how MELTING can be used to construct more ambitious programs. AVAILABILITY: MELTING is available for several platforms (http://www.pasteur.fr/recherche/unites/neubiomol/meltinghome.html) and is accessible via a www server (http://bioweb.pasteur.fr/seqanal/interfaces/melting.html). CONTACT: [email protected]

Abstract Summary: StochSim is a stochastic simulator for chemical reactions. Molecules are represented as individual software objects that react according to probabilities derived from concentrations and rate constants. Version 1.2 of StochSim provides a novel cross-platform graphical interface written in Perl/Tk. A simple two-dimensional spatial structure has also been implemented, in which nearest-neighbour interactions of molecules in a 2-D lattice can be simulated. Availability: Various ports of the program can be retrieved at ftp://ftp.cds.caltech.edu/pub/dbray/ Contact: [email protected]; [email protected] * To whom correspondence should be addressed.