Wolfram Liebermeister

Wolfram Liebermeister
French National Institute for Agriculture, Food, and Environment (INRAE) | INRAE · MathNum

Dr. rer. nat. (Theoretical Biophysics)

About

103
Publications
51,030
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Introduction
My current research projects concern the economy of the cell, for example the prediction of protein investments in living cells, based on computational metabolic models. For more information, please see /www.metabolic-economics.de
Additional affiliations
September 2011 - August 2016
Charité Universitätsmedizin Berlin
Position
  • Researcher
Description
  • DFG-funded project "Dynamics and function of enzyme regulation in large metabolic networks", https://www.metabolic-economics.de/liebermeister/project-dynamics-and-function.html
December 2010 - May 2011
Weizmann Institute of Science
Position
  • Researcher
March 2009 - September 2010
Humboldt-Universität zu Berlin
Position
  • PostDoc Position

Publications

Publications (103)
Book
Full-text available
Retrieving, processing, tracking and tracing have evolved into standard actions performed with any available data, including their instant translation into images, thus transforming, modifying and adjusting them for the visualized results. Data are treated as fragments; aspects, parameters, details of complex actions and behavior, which are isolate...
Article
Full-text available
Computational models have great potential to accelerate bioscience, bioengineering, and medicine. However, it remains challenging to reproduce and reuse simulations, in part, because the numerous formats and methods for simulating various subsystems and scales remain siloed by different software tools. For example, each tool must be executed throug...
Preprint
Full-text available
Computational models have great potential to accelerate bioscience, bioengineering, and medicine. However, it remains challenging to reproduce and reuse simulations, in part, because the numerous formats and methods for simulating various subsystems and scales remain siloed by different software tools. For example, each tool must be executed throug...
Article
Full-text available
Enzyme kinetic constants in vivo are largely unknown, which limits the construction of large metabolic models. Given measured metabolic fluxes, metabolite concentrations, and enzyme concentrations, these constants may be inferred by model fitting, but the estimation problems are hard to solve if models are large. Here we show how consistent kinetic...
Article
Full-text available
Some biological networks exhibit oscillations in their components to convert stimuli to time-dependent responses. The eukaryotic cell cycle is such a case, being governed by waves of cyclin-dependent kinase (cyclin/Cdk) activities that rise and fall with specific timing and guarantee its timely occurrence. Disruption of cyclin/Cdk oscillations coul...
Article
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Abstract Systems biology has experienced dramatic growth in the number, size, and complexity of computational models. To reproduce simulation results and reuse models, researchers must exchange unambiguous model descriptions. We review the latest edition of the Systems Biology Markup Language (SBML), a format designed for this purpose. A community...
Preprint
Full-text available
A central challenge in science is to understand how behaviors emerge from complex networks. This often requires reusing and integrating heterogeneous information. Supplementary spreadsheets to journal articles are a key data source. Spreadsheets are popular because they are easy to read and write. However, spreadsheets are often difficult to reanal...
Preprint
Full-text available
Enzyme kinetic constants in vivo are largely unknown, which limits the construction of large metabolic models. In theory, kinetic constants can be fitted to measured metabolic fluxes, metabolite concentrations, and enzyme concentrations, but these estimation problems are typically non-convex. This makes them hard to solve, especially if models are...
Article
Resource Balance Analysis (RBA) is a computational method based on resource allocation, which performs accurate quantitative predictions of whole-cell states (i.e. growth rate, metabolic fluxes, abundances of molecular machines including enzymes) across growth conditions. We present an integrated workflow of RBA together with the Python package RBA...
Preprint
Full-text available
Resource Balance Analysis (RBA) is a computational method based on resource allocation, which performs accurate quantitative predictions of whole-cell states (i.e. growth rate, meta-bolic fluxes, abundances of molecular machines including enzymes) across growth conditions. We present an integrated workflow of RBA together with the Python package RB...
Article
Full-text available
Measured kinetic constants are key input data for metabolic models, but they are often uncertain, inconsistent, and incomplete. Parameter balancing translates such data into complete and consistent parameter sets while accounting for predefined ranges and physical constraints. Based on Bayesian regression, it determines a most plausible parameter s...
Preprint
Full-text available
Cells need to make an efficient use of metabolites, proteins, energy, membrane space, and time, and resource allocation is also an important aspect of metabolism. How, for example, should cells distribute their protein budget between different cellular functions, e.g. different metabolic pathways, to maximise growth? Cellular resource allocation ca...
Preprint
Full-text available
To improve their metabolic performance, cells have to realise good compromises between large production fluxes, low enzyme investments, and well-adapted metabolite levels. In models, this idea can be formulated in the form of optimality principles that trade a high metabolic benefit against low enzyme cost. However, different modelling approaches a...
Article
Full-text available
How individual enzymes evolved is relatively well understood. However, individual enzymes rarely confer a physiological advantage on their own. Judging by its current state, the emergence of metabolism seemingly demanded the simultaneous emergence of many enzymes. Indeed, how multicomponent interlocked systems, like metabolic pathways, evolved is l...
Article
Full-text available
Microbes may maximize the number of daughter cells per time or per amount of nutrients consumed. These two strategies correspond, respectively, to the use of enzyme-efficient or substrate-efficient metabolic pathways. In reality, fast growth is often associated with wasteful, yield-inefficient metabolism, and a general thermodynamic trade-off betwe...
Preprint
Full-text available
Microbes may maximize the number of daughter cells per time or per amount of nutrients consumed. These two strategies correspond, respectively, to the use of enzyme-efficient or substrate-efficient metabolic pathways. In reality, fast growth is often associated with wasteful, yield-inefficient metabolism, and a general thermodynamic trade-off betwe...
Article
Metabolic fluxes in cells are governed by physical, biochemical, physiological, and economic principles. Cells may show "economical" behaviour, trading metabolic performance against the costly side-effects of high enzyme or metabolite concentrations. Some constraint-based flux prediction methods score fluxes by heuristic flux costs as proxies of en...
Article
Full-text available
Systems biology models are rapidly increasing in complexity, size and numbers. When building large models, researchers rely on software tools for the retrieval, comparison, combination and merging of models, as well as for version control. These tools need to be able to quantify the differences and similarities between computational models. However...
Data
Supplementary material text containing Figure A—Figure F and Table A—Table C. (PDF)
Article
Full-text available
Systems biology models are rapidly increasing in complexity, size and numbers. When building large models, researchers rely on software tools for the retrieval, comparison, combination and merging of models, as well as for version control. These tools need to be able to quantify the differences and similarities between computational models. However...
Article
Full-text available
Methods: We organized the 2015 Whole-Cell Modeling Summer School to teach WC modeling and evaluate the need for new WC modeling standards and software by recoding a recently published WC model in SBML. Results: Our analysis revealed several challenges to representing WC models using the current standards. Conclusion: We, therefore, propose sev...
Article
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Availability and implementation: SBtab documents can be created and edited with any text editor or spreadsheet tool. The website www.sbtab.net provides online tools for syntax validation and conversion to SBML and HTML, as well as software for using SBtab in MS Excel, MATLAB and R. The stand-alone Python code contains functions for file parsing, v...
Article
Full-text available
Bacterial growth depends crucially on metabolic fluxes, which are limited by the cell's capacity to maintain metabolic enzymes. The necessary enzyme amount per unit flux is a major determinant of metabolic strategies both in evolution and bioengineering. It depends on enzyme parameters (such as kcat and KM constants), but also on metabolite concent...
Article
Full-text available
Turnover numbers, also known as kcat values, are fundamental properties of enzymes. However, kcat data are scarce and measured in vitro, thus may not faithfully represent the in vivo situation. A basic question that awaits elucidation is: how representative are kcat values for the maximal catalytic rates of enzymes in vivo? Here, we harness omics d...
Article
Full-text available
Periodic enzyme activities can improve the metabolic performance of cells. As an adaptation to periodic environments or by driving metabolic cycles that can shift fluxes and rearrange metabolic processes in time to increase their efficiency. To study what benefits can ensue from rhythmic gene expression or posttranslational modification of enzymes,...
Article
Full-text available
Constructing a model in a hierarchical fashion is a natural approach to managing model complexity, and offers additional opportunities such as the potential to re-use model components. The SBML Level 3 Version 1 Core specification does not directly provide a mechanism for defining hierarchical models, but it does provide a mechanism for SBML packag...
Article
Full-text available
Constructing a model in a hierarchical fashion is a natural approach to managing model complexity, and offers additional opportunities such as the potential to re-use model components. The SBML Level 3 Version 1 Core specification does not directly provide a mechanism for defining hierarchical models, but it does provide a mechanism for SBML packag...
Article
Full-text available
Data tables in the form of spreadsheets or delimited text files are the most utilised data format in Systems Biology. However, they are often not sufficiently structured and lack clear naming conventions that would be required for modelling. We propose the SBtab format as an attempt to establish an easy-to-use table format that is both flexible and...
Article
Enzyme costs play a major role in the choice of metabolic routes, both in evolution and bioengineering. Given desired fluxes, necessary enzyme levels can be estimated based on known rate laws and on a principle of minimal enzyme cost. With logarithmic metabolite levels as free variables, enzyme cost functions and constraints in optimality and sampl...
Article
Full-text available
Proteomics techniques generate an avalanche of data and promise to satisfy biologists' long-held desire to measure absolute protein abundances on a genome-wide scale. However, can this knowledge be translated into a clearer picture of how cells invest their protein resources? This article aims to give a broad perspective on the composition of prote...
Article
Metabolic systems are governed by a compromise between metabolic benefit and enzyme cost. This hypothesis and its consequences can be studied by kinetic models in which enzyme profiles are chosen by optimality principles. In enzyme-optimal states, active enzymes must provide benefits: a higher enzyme level must provide a metabolic benefit to justif...
Article
Metabolic fluxes are governed by physical and economic principles. Stationarity constrains them to a subspace in flux space and thermodynamics makes them lead from higher to lower chemical potentials. At the same time, fluxes in cells represent a compromise between metabolic performance and enzyme cost. To capture this, some flux prediction methods...
Article
Full-text available
In metabolism research, thermodynamics is usually used to determine the directionality of a reaction or the feasibility of a pathway. However, the relationship between thermodynamic potentials and fluxes is not limited to questions of directionality: thermodynamics also affects the kinetics of reactions through the flux-force relationship, which st...
Article
Full-text available
The quantitative effects of environmental and genetic perturbations on metabolism can be studied in silico using kinetic models. We present a strategy for large-scale model construction based on a logical layering of data such as reaction fluxes, metabolite concentrations, and kinetic constants. The resulting models contain realistic standard rate...
Article
Full-text available
In the context of SBML, “hierarchical model composition” refers to the ability to include models as submodels inside another model. The goal is to support the ability of modelers and software tools to do such things as (1) decompose larger models into smaller ones, as a way to manage complexity; (2) incorporate multiple instances of a given model...
Article
Full-text available
Steady-state metabolite concentrations in a microorganism typically span several orders of magnitude. The underlying principles governing these concentrations remain poorly understood. Here, we hypothesize that observed variation can be explained in terms of a compromise between factors that favor minimizing metabolite pool sizes (e.g. limited solv...
Article
Metabolic networks can be turned into kinetic models in a predefined steady state by sampling the reaction elasticities in this state. Elasticities for many reversible rate laws can be computed from the reaction Gibbs free energies, which are determined by the state, and from physically unconstrained saturation values. Starting from a network struc...
Article
Full-text available
Michaelis and Menten's mechanism for enzymatic catalysis is remarkable both in its simplicity and its wide applicability. The extension for reversible processes, as done by Haldane, makes it even more relevant as most enzymes catalyze reactions that are reversible in nature and carry in vivo flux in both directions. Here, we decompose the reversibl...
Article
Full-text available
Contrary to the textbook portrayal of glycolysis as a single pathway conserved across all domains of life, not all sugar-consuming organisms use the canonical Embden-Meyerhoff-Parnass (EMP) glycolytic pathway. Prokaryotic glucose metabolism is particularly diverse, including several alternative glycolytic pathways, the most common of which is the E...
Article
Full-text available
Protein levels are a dominant factor shaping natural and synthetic biological systems. Although proper functioning of metabolic pathways relies on precise control of enzyme levels, the experimental ability to balance the levels of many genes in parallel is a major outstanding challenge. Here, we introduce a rapid and modular method to span the expr...
Article
Full-text available
Adaptation of cells to environmental changes requires dynamic interactions between metabolic and regulatory networks, but studies typically address only one or a few layers of regulation. For nutritional shifts between two preferred carbon sources of Bacillus subtilis, we combined statistical and model-based data analyses of dynamic transcript, pro...
Article
Full-text available
Bacteria adapt to environmental stimuli by adjusting their transcriptomes in a complex manner, the full potential of which has yet to be established for any individual bacterial species. Here, we report the transcriptomes of Bacillus subtilis exposed to a wide range of environmental and nutritional conditions that the organism might encounter in na...
Article
Full-text available
To enable automatic searches, alignments, and model combination, the elements of systems biology models need to be compared and matched across models. Elements can be identified by machine-readable biological annotations, but assigning such annotations and matching non-annotated elements is tedious work and calls for automation. A new method called...
Article
A variety of three-dimensional geometric structures can be formed by regular triangles that are flexibly connected along their edges. Polyhedra, chains, closed rings, and spatial networks can be built by interlinking building blocks called “corpuscles”, each composed of a small number of triangles. Due to the flexible edges, some of the resulting s...
Article
Systems biology models can be reused within new simulation scenarios, as parts of more complex models or as sources of biochemical knowledge. Reusability does not come by itself but has to be ensured while creating a model. Most important, models should be designed to remain valid in different contexts-for example, for different experimental condit...
Data
In the Appendix we present a number of model similarity measures and evaluate their use for unsupervised clustering. Furthermore, we demonstrate how a similarity search can be used for tiling the yeast metabolic network with kinetic models
Article
Full-text available
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 experimenta...
Article
Full-text available
The annotation of Systems Biology Markup Language (SBML) models with semantic terms has been supported for a number of years. The prevalence of such annotated models is growing, with repositories such as Biomodels.net and an increasing number of software tools supporting and encouraging their use and development. With the increasing use of semanti...
Article
Kinetic modeling of metabolic pathways has become a major field of systems biology. It combines structural information about metabolic pathways with quantitative enzymatic rate laws. Some of the kinetic constants needed for a model could be collected from ever-growing literature and public web resources, but they are often incomplete, incompatible,...
Article
Full-text available
A number of new functions in the software tool semanticSBML make extensive use of MIRIAM-compliant annotations in SBML models. Semantic model search allows to obtain, from BioModels Database, a ranked list of models resembling a given query model or data set. Model clustering allows for exploring and visualising similarities among large numbers of...
Article
Full-text available
Motivation: The availability of modern sequencing techniques has led to a rapid increase in the amount of reconstructed metabolic networks. Using these models as a platform for the analysis of high throughput transcriptomic, proteomic and metabolomic data can provide valuable insight into conditional changes in the metabolic activity of an organism...
Article
Full-text available
Standard rate laws are a key requisite for systematically turning metabolic networks into kinetic models. They should provide simple, general and biochemically plausible formulae for reaction velocities and reaction elasticities. At the same time, they need to respect thermodynamic relations between the kinetic constants and the metabolic fluxes an...
Article
Full-text available
Yeast cells live in a highly fluctuating environment with respect to temperature, nutrients, and especially osmolarity. The Hog1 mitogen-activated protein kinase (MAPK) pathway is crucial for the adaption of yeast cells to external osmotic changes. To better understand the osmo-adaption mechanism in the budding yeast Saccharomyces cerevisiae, we ha...
Conference Paper
Full-text available
semanticSBML 2.0 is an online collection of services for the work with biochemical network models in SBML format. Comment: in Adrian Paschke, Albert Burger, Andrea Splendiani, M. Scott Marshall, Paolo Romano: Proceedings of the 3rd International Workshop on Semantic Web Applications and Tools for the Life Sciences, Berlin,Germany, December 8-10, 20...
Article
Full-text available
Systems Biology Markup Language (SBML) is the leading exchange format for mathematical models in Systems Biology. Semantic annotations link model elements with external knowledge via unique database identifiers and ontology terms, enabling software to check and process models by their biochemical meaning. Such information is essential for model mer...
Article
Full-text available
The BioModels database contains biochemical network models in SBML format, in which the biochemical meaning of elements is specified by MIRIAM-compliant RDF annotations. We used these annotations to define a similarity measure for models, scoring the overlap of the biochemical systems described. Based on this score, we used two-way clustering to de...
Article
The BioModels database contains biochemical network models in SBML format, in which the biochemical meaning of elements is specified by MIRIAM-compliant RDF annotations. We used these annotations to define a similarity measure for models, scoring the overlap of the biochemical systems described. Based on this score, we used two-way clustering to de...