Creation and analysis of biochemical constraint-based models using the COBRA Toolbox v.3.0.

in Nature protocols (2019), 14(3), 639-702

Constraint-based reconstruction and analysis (COBRA) provides a molecular mechanistic framework for integrative analysis of experimental molecular systems biology data and quantitative prediction of ... [more ▼]

Constraint-based reconstruction and analysis (COBRA) provides a molecular mechanistic framework for integrative analysis of experimental molecular systems biology data and quantitative prediction of physicochemically and biochemically feasible phenotypic states. The COBRA Toolbox is a comprehensive desktop software suite of interoperable COBRA methods. It has found widespread application in biology, biomedicine, and biotechnology because its functions can be flexibly combined to implement tailored COBRA protocols for any biochemical network. This protocol is an update to the COBRA Toolbox v.1.0 and v.2.0. Version 3.0 includes new methods for quality-controlled reconstruction, modeling, topological analysis, strain and experimental design, and network visualization, as well as network integration of chemoinformatic, metabolomic, transcriptomic, proteomic, and thermochemical data. New multi-lingual code integration also enables an expansion in COBRA application scope via high-precision, high-performance, and nonlinear numerical optimization solvers for multi-scale, multi-cellular, and reaction kinetic modeling, respectively. This protocol provides an overview of all these new features and can be adapted to generate and analyze constraint-based models in a wide variety of scenarios. The COBRA Toolbox v.3.0 provides an unparalleled depth of COBRA methods. [less ▲]

The intertwined metabolism during symbiotic nitrogen fixation elucidated by metabolic modelling

in Scientific Reports (2018), 8

Genome-scale metabolic network models can be used for various analyses including the prediction of metabolic responses to changes in the environment. Legumes are well known for their rhizobial symbiosis ... [more ▼]

Genome-scale metabolic network models can be used for various analyses including the prediction of metabolic responses to changes in the environment. Legumes are well known for their rhizobial symbiosis that introduces nitrogen into the global nutrient cycle. Here, we describe a fully compartmentalised, mass and charge-balanced, genome-scale model of the clover Medicago truncatula, which has been adopted as a model organism for legumes. We employed flux balance analysis to demonstrate that the network is capable of producing biomass components in experimentally observed proportions, during day and night. By connecting the plant model to a model of its rhizobial symbiont, Sinorhizobium meliloti, we were able to investigate the effects of the symbiosis on metabolic fluxes and plant growth and could demonstrate how oxygen availability influences metabolic exchanges between plant and symbiont, thus elucidating potential benefits of inter organism amino acid cycling. We thus provide a modelling framework, in which the interlinked metabolism of plants and nodules can be studied from a theoretical perspective. [less ▲]

Constraint based modelling going multicellular

in Frontiers in Molecular Biosciences (2016), 3(3),

Constraint based modelling has seen applications in many microorganisms. For example, there are now established methods to determine potential genetic modifications and external interventions to increase ... [more ▼]

Constraint based modelling has seen applications in many microorganisms. For example, there are now established methods to determine potential genetic modifications and external interventions to increase the efficiency of microbial strains in chemical production pipelines. In addition, multiple models of multicellular organisms have been created including plants and humans. While initially the focus here was on modelling individual cell types of the multicellular organism, this focus recently started to switch. Models of microbial communities, as well as multitissue models of higher organisms have been constructed. These models thereby can include different parts of a plant, like root, stem or different tissue types in the same organ. Such models can elucidate details of the interplay between symbiotic organisms, as well as the concerted efforts of multiple tissues and can be applied to analyse the effects of drugs or mutations on a more systemic level. In this review we give an overview of the recent development of multi-tissue models using constraint based techniques and the methods employed when investigating these models. We further highlight advances in combining constraint based models with dynamic and regulatory information and give an overview of these types of hybrid or multi-level approaches. [less ▲]

Towards improved genome-scale metabolic network reconstructions: unification, transcript specificity and beyond.

in Briefings in bioinformatics (2015)

Genome-scale metabolic network reconstructions provide a basis for the investigation of the metabolic properties of an organism. There are reconstructions available for multiple organisms, from ... [more ▼]

Genome-scale metabolic network reconstructions provide a basis for the investigation of the metabolic properties of an organism. There are reconstructions available for multiple organisms, from prokaryotes to higher organisms and methods for the analysis of a reconstruction. One example is the use of flux balance analysis to improve the yields of a target chemical, which has been applied successfully. However, comparison of results between existing reconstructions and models presents a challenge because of the heterogeneity of the available reconstructions, for example, of standards for presenting gene-protein-reaction associations, nomenclature of metabolites and reactions or selection of protonation states. The lack of comparability for gene identifiers or model-specific reactions without annotated evidence often leads to the creation of a new model from scratch, as data cannot be properly matched otherwise. In this contribution, we propose to improve the predictive power of metabolic models by switching from gene-protein-reaction associations to transcript-isoform-reaction associations, thus taking advantage of the improvement of precision in gene expression measurements. To achieve this precision, we discuss available databases that can be used to retrieve this type of information and point at issues that can arise from their neglect. Further, we stress issues that arise from non-standardized building pipelines, like inconsistencies in protonation states. In addition, problems arising from the use of non-specific cofactors, e.g. artificial futile cycles, are discussed, and finally efforts of the metabolic modelling community to unify model reconstructions are highlighted. [less ▲]

Systems approaches to modelling pathways and networks

in Briefings in Functional Genomics (2011), 10(5), 266-279

It has become commonly accepted that systems approaches to biology are of outstanding importance to gain understanding from the vast amount of data which is presently being generated by advancing high ... [more ▼]

It has become commonly accepted that systems approaches to biology are of outstanding importance to gain understanding from the vast amount of data which is presently being generated by advancing high-throughput technologies. The diversity of methods to model pathways and networks has significantly expanded over the past two decades. Modern and traditional approaches are equally important and recent activities aim at integrating the advantages of both. While traditional methods, based on differential equations, are useful to study the dynamics of small systems, modern constraint-based models can be applied to genome-scale systems, but are not able to capture dynamic features. Integrating different approaches is important to develop consistent theoretical descriptions encompassing various scales of biological information. The rapid progress of the field of theoretical systems biology, however, demonstrates how our fundamental theoretical understanding of biology is gaining momentum. The scientific community has apparently accepted the challenge to truly understand the principles of life. [less ▲]