Simulation Of Metabolic Networks Research Articles

Principles of metabolome conservation in animals

Metabolite levels shape cellular physiology and disease susceptibility, yet the general principles governing metabolome evolution are largely unknown. Here, we introduce a measure of conservation of individual metabolite levels among related species. By analyzing multispecies tissue metabolome datasets in phylogenetically diverse mammals and fruit flies, we show that conservation varies extensively across metabolites. Three major functional properties, metabolite abundance, essentiality, and association with human diseases predict conservation, highlighting a striking parallel between the evolutionary forces driving metabolome and protein sequence conservation. Metabolic network simulations recapitulated these general patterns and revealed that abundant metabolites are highly conserved due to their strong coupling to key metabolic fluxes in the network. Finally, we show that biomarkers of metabolic diseases can be distinguished from other metabolites simply based on evolutionary conservation, without requiring any prior clinical knowledge. Overall, this study uncovers simple rules that govern metabolic evolution in animals and implies that most tissue metabolome differences between species are permitted, rather than favored by natural selection. More broadly, our work paves the way toward using evolutionary information to identify biomarkers, as well as to detect pathogenic metabolome alterations in individual patients.

In silico genome-scale metabolic modeling and in vitro static time-kill studies of exogenous metabolites alone and with polymyxin B against Klebsiella pneumoniae.

Multidrug-resistant (MDR) Klebsiella pneumoniae is a top-prioritized Gram-negative pathogen with a high incidence in hospital-acquired infections. Polymyxins have resurged as a last-line therapy to combat Gram-negative “superbugs”, including MDR K. pneumoniae. However, the emergence of polymyxin resistance has increasingly been reported over the past decades when used as monotherapy, and thus combination therapy with non-antibiotics (e.g., metabolites) becomes a promising approach owing to the lower risk of resistance development. Genome-scale metabolic models (GSMMs) were constructed to delineate the altered metabolism of New Delhi metallo-β-lactamase- or extended spectrum β-lactamase-producing K. pneumoniae strains upon addition of exogenous metabolites in media. The metabolites that caused significant metabolic perturbations were then selected to examine their adjuvant effects using in vitro static time–kill studies. Metabolic network simulation shows that feeding of 3-phosphoglycerate and ribose 5-phosphate would lead to enhanced central carbon metabolism, ATP demand, and energy consumption, which is converged with metabolic disruptions by polymyxin treatment. Further static time–kill studies demonstrated enhanced antimicrobial killing of 10 mM 3-phosphoglycerate (1.26 and 1.82 log10 CFU/ml) and 10 mM ribose 5-phosphate (0.53 and 0.91 log10 CFU/ml) combination with 2 mg/L polymyxin B against K. pneumoniae strains. Overall, exogenous metabolite feeding could possibly improve polymyxin B activity via metabolic modulation and hence offers an attractive approach to enhance polymyxin B efficacy. With the application of GSMM in bridging the metabolic analysis and time–kill assay, biological insights into metabolite feeding can be inferred from comparative analyses of both results. Taken together, a systematic framework has been developed to facilitate the clinical translation of antibiotic-resistant infection management.

A Siamese neural network model for the prioritization of metabolic disorders by integrating real and simulated data.

Untargeted metabolomic approaches hold a great promise as a diagnostic tool for inborn errors of metabolisms (IEMs) in the near future. However, the complexity of the involved data makes its application difficult and time consuming. Computational approaches, such as metabolic network simulations and machine learning, could significantly help to exploit metabolomic data to aid the diagnostic process. While the former suffers from limited predictive accuracy, the latter is normally able to generalize only to IEMs for which sufficient data are available. Here, we propose a hybrid approach that exploits the best of both worlds by building a mapping between simulated and real metabolic data through a novel method based on Siamese neural networks (SNN). The proposed SNN model is able to perform disease prioritization for the metabolic profiles of IEM patients even for diseases that it was not trained to identify. To the best of our knowledge, this has not been attempted before. The developed model is able to significantly outperform a baseline model that relies on metabolic simulations only. The prioritization performances demonstrate the feasibility of the method, suggesting that the integration of metabolic models and data could significantly aid the IEM diagnosis process in the near future. Metabolic datasets used in this study are publicly available from the cited sources. The original data produced in this study, including the trained models and the simulated metabolic profiles, are also publicly available (Messa et al., 2020).

IN SILICO GENOME-SCALE RECONSTRUCTION AND ANALYSIS OF THE SHEWANELLA LOIHICA PV-4 METABOLIC NETWORK

Microbial Fuel Cells (MFCs) are devices that generate electricity directly from organic compounds with microbes (electricigens) serving as anodic catalysts. As a novel environment-friendly energy source, MFCs have extensive practical value. Since the biological features and metabolic mechanism of electricigens have a great effect on the electricity production of MFCs, it is a big deal to screen strains with high electricity productivity for improving the power output of MFC. Reconstructions and simulations of metabolic networks are of significant help in studying the metabolism of microorganisms so as to guide gene engineering and metabolic engineering to improve their power-generating efficiency. Herein, we reconstructed a genome-scale constraint-based metabolic network model of Shewanella loihica PV-4, an important electricigen, based on its genomic functional annotations, reaction databases and published metabolic network models of seven microorganisms. The resulting network model iGX790 consists of 902 reactions (including 71 exchange reactions), 798 metabolites and 790 genes, covering the main pathways such as carbon metabolism, energy metabolism, amino acid metabolism, nucleic acid metabolism and lipid metabolism. Using the model, we simulated the growth rate, the maximal synthetic rate of ATP, the flux variability analysis of metabolic network, gene deletion and so on to examine the metabolism of S. loihica PV-4.

A Mobile-Based Diet Monitoring System for Obesity Management.

Personal diet management is key to fighting the obesity epidemic. Recent advances in smartphones and wearable sensor technologies have empowered automated food monitoring through food image processing and eating episode detection, with the goal to conquer drawbacks of traditional food journaling that is labour intensive, inaccurate, and low adherent. In this paper, we present a new interactive mobile system that enables automated food recognition and assessment based on user food images and provides dietary intervention while tracking users' dietary and physical activities. In addition to using techniques in computer vision and machine learning, one unique feature of this system is the realization of real-time energy balance monitoring through metabolic network simulation. As a proof of concept, we have demonstrated the use of this system through an Android application.

PASMet: a web-based platform for prediction, modelling and analyses of metabolic systems.

PASMet (Prediction, Analysis and Simulation of Metabolic networks) is a web-based platform for proposing and verifying mathematical models to understand the dynamics of metabolism. The advantages of PASMet include user-friendliness and accessibility, which enable biologists and biochemists to easily perform mathematical modelling. PASMet offers a series of user-functions to handle the time-series data of metabolite concentrations. The functions are organised into four steps: (i) Prediction of a probable metabolic pathway and its regulation; (ii) Construction of mathematical models; (iii) Simulation of metabolic behaviours; and (iv) Analysis of metabolic system characteristics. Each function contains various statistical and mathematical methods that can be used independently. Users who may not have enough knowledge of computing or programming can easily and quickly analyse their local data without software downloads, updates or installations. Users only need to upload their files in comma-separated values (CSV) format or enter their model equations directly into the website. Once the time-series data or mathematical equations are uploaded, PASMet automatically performs computation on server-side. Then, users can interactively view their results and directly download them to their local computers. PASMet is freely available with no login requirement at http://pasmet.riken.jp/ from major web browsers on Windows, Mac and Linux operating systems.

Reconstruction and applications of consensus yeast metabolic network based on RNA sequencing.

One practical application of genome‐scale metabolic reconstructions is to interrogate multispecies relationships. Here, we report a consensus metabolic model in four yeast species (Saccharomyces cerevisiae, S. paradoxus, S. mikatae, and S. bayanus) by integrating metabolic network simulations with RNA sequencing (RNA‐seq) datasets. We generated high‐resolution transcriptome maps of four yeast species through de novo assembly and genome‐guided approaches. The transcriptomes were annotated and applied to build the consensus metabolic network, which was verified using independent RNA‐seq experiments. The expression profiles reveal that the genes involved in amino acid and lipid metabolism are highly coexpressed. The diverse phenotypic characteristics, such as cellular growth and gene deletions, can be simulated using the metabolic model. We also explored the applications of the consensus model in metabolic engineering using yeast‐specific reactions and biofuel production as examples. Similar strategies will benefit communities studying genome‐scale metabolic networks of other organisms.

Analysis of Sensitive CO2 Pathways and Genes Related to Carbon Uptake and Accumulation in Chlamydomonas reinhardtii through Genomic Scale Modeling and Experimental Validation.

The development of microalgae sustainable applications needs better understanding of microalgae biology. Moreover, how cells coordinate their metabolism toward biomass accumulation is not fully understood. In this present study, flux balance analysis (FBA) was performed to identify sensitive metabolic pathways of Chlamydomonas reinhardtii under varied CO2 inputs. The metabolic network model of Chlamydomonas was updated based on the genome annotation data and sensitivity analysis revealed CO2 sensitive reactions. Biological experiments were performed with cells cultivated at 0.04% (air), 2.5, 5, 8, and 10% CO2 concentration under controlled conditions and cell growth profiles and biomass content were measured. Pigments, lipids, proteins, and starch were further quantified for the reference low (0.04%) and high (10%) CO2 conditions. The expression level of candidate genes of sensitive reactions was measured and validated by quantitative real time PCR. The sensitive analysis revealed mitochondrial compartment as the major affected by changes on the CO2 concentrations and glycolysis/gluconeogenesis, glyoxylate, and dicarboxylate metabolism among the affected metabolic pathways. Genes coding for glycerate kinase (GLYK), glycine cleavage system, H-protein (GCSH), NAD-dependent malate dehydrogenase (MDH3), low-CO2 inducible protein A (LCIA), carbonic anhydrase 5 (CAH5), E1 component, alpha subunit (PDC3), dual function alcohol dehydrogenase/acetaldehyde dehydrogenase (ADH1), and phosphoglucomutase (GPM2), were defined, among other genes, as sensitive nodes in the metabolic network simulations. These genes were experimentally responsive to the changes in the carbon fluxes in the system. We performed metabolomics analysis using mass spectrometry validating the modulation of carbon dioxide responsive pathways and metabolites. The changes on CO2 levels mostly affected the metabolism of amino acids found in the photorespiration pathway. Our updated metabolic network was compared to previous model and it showed more consistent results once considering the experimental data. Possible roles of the sensitive pathways in the biomass metabolism are discussed.

A holistic approach for integration of biological systems and usage in drug discovery

A system can be defined as an organized, interconnected structure consisting of interrelated and interdependent elements (e.g., components, factors, members, parts). These parts and processes are connected by structural and/or behavioral relationships and continually influence one another directly or indirectly to maintain a balance essential for the existence of the system, and for achieving its goal. With increasing inflow of biological data, serious efforts to empathize biological systems as true systems are nowadays almost practicable. Handling high-throughput data places stress mainly on in silico approach comprising database handling, modeling, simulation and analysis, resulting in dramatic progress in system-level analysis. The databases and methods in bioinformatics are now moving in the direction of implementation of integrative dataset systems to represent genes, proteins and metabolic pathways in combination with simulated environment which is dynamic. For understanding the complex biological disorders and normal pathways of system it is significant to integrate the reductionist data which comes from transcriptomics, genomics, proteomics, lipidomics, glycomics, fluxomics and metabolomics. Numerous bioinformatics approaches are being exploited to integrate the molecular information from the biological databases and assist in simulation of metabolic networks. High-throughput experimental data set systems are, however, established on the static representation of the molecular data and existing knowledge. Various biological tools have been developed for understanding the mechanism of several diseases for drug discovery process. Study of dynamic nature of genetic, biochemical and signal transduction pathways can be done by simulating reactions with the help of integrative tools. Rising usage of rational drug designing approach is significant for identification of target in disease polluted network and evaluating ligand interaction for enhanced efficacy. How in-depth investigation of the whole system (a holistic approach) leads to emergence of systems biology is the crux of this review.

An approach to multiscale modelling with graph grammars.

Functional-structural plant models (FSPMs) simulate biological processes at different spatial scales. Methods exist for multiscale data representation and modification, but the advantages of using multiple scales in the dynamic aspects of FSPMs remain unclear. Results from multiscale models in various other areas of science that share fundamental modelling issues with FSPMs suggest that potential advantages do exist, and this study therefore aims to introduce an approach to multiscale modelling in FSPMs. A three-part graph data structure and grammar is revisited, and presented with a conceptual framework for multiscale modelling. The framework is used for identifying roles, categorizing and describing scale-to-scale interactions, thus allowing alternative approaches to model development as opposed to correlation-based modelling at a single scale. Reverse information flow (from macro- to micro-scale) is catered for in the framework. The methods are implemented within the programming language XL. Three example models are implemented using the proposed multiscale graph model and framework. The first illustrates the fundamental usage of the graph data structure and grammar, the second uses probabilistic modelling for organs at the fine scale in order to derive crown growth, and the third combines multiscale plant topology with ozone trends and metabolic network simulations in order to model juvenile beech stands under exposure to a toxic trace gas. The graph data structure supports data representation and grammar operations at multiple scales. The results demonstrate that multiscale modelling is a viable method in FSPM and an alternative to correlation-based modelling. Advantages and disadvantages of multiscale modelling are illustrated by comparisons with single-scale implementations, leading to motivations for further research in sensitivity analysis and run-time efficiency for these models.

SS-mPMG and SS-GA: Tools for Finding Pathways and Dynamic Simulation of Metabolic Networks

Metabolomics analysis tools can provide quantitative information on the concentration of metabolites in an organism. In this paper, we propose the minimum pathway model generator tool for simulating the dynamics of metabolite concentrations (SS-mPMG) and a tool for parameter estimation by genetic algorithm (SS-GA). SS-mPMG can extract a subsystem of the metabolic network from the genome-scale pathway maps to reduce the complexity of the simulation model and automatically construct a dynamic simulator to evaluate the experimentally observed behavior of metabolites. Using this tool, we show that stochastic simulation can reproduce experimentally observed dynamics of amino acid biosynthesis in Arabidopsis thaliana. In this simulation, SS-mPMG extracts the metabolic network subsystem from published databases. The parameters needed for the simulation are determined using a genetic algorithm to fit the simulation results to the experimental data. We expect that SS-mPMG and SS-GA will help researchers to create relevant metabolic networks and carry out simulations of metabolic reactions derived from metabolomics data.

Understanding traditional Chinese medicine anti-inflammatory herbal formulae by simulating their regulatory functions in the human arachidonic acid metabolic network

Through history, traditional Chinese medicine (TCM) has adopted oriental philosophical practices of drug combination and interaction to address human diseases. To investigate this from a systems biology point of view, we analysed 28 TCM herbs for their anti-inflammatory function, using molecular docking and arachidonic acid (AA) metabolic network simulation. The inhibition potential of each herb toward five essential enzymes as well as their possible side effects were examined. Three commonly prescribed anti-inflammatory formulae were simulated to discover the combinatorial properties of each contained herb in regulating the whole metabolic network. We discovered that different ingredients of a formula tend to inhibit different targets, which almost covered all the targets in the whole network. We also found that herbal combinations could achieve the same therapeutic effect at lower doses compared with individual usage. New herbal combinations were also predicted based on the inhibition potentials and two types of synergistic drug combinations of TCM theory were discussed from the perspective of systems biology. Using this combined approach of molecular docking and network simulation, we were able to computationally elucidate the combinatorial effects of TCM to intervene disease networks. We expect novel TCM formulae or modern drug combinations to be developed based on this research.

What is the true enzyme kinetics in the biological system? An investigation of macromolecular crowding effect upon enzyme kinetics of glucose-6-phosphate dehydrogenase

Enzyme kinetic parameters for rate equations are vital in metabolic network simulation, a major part of systems biology research efforts. Measurements of Michaelis–Menten kinetic parameters K m and K cat have been performed for enzymes glucose-6-phosphate dehydrogenase (G6P DH) under crowded conditions using molecular crowding agents bovine serum albumin (BSA) and polyethylene glycol (PEG) of 8000 Da molecular weight. An increase in K cat was observed at very low concentrations of crowding agent, and also at high crowder concentrations when the experiment was performed at 45 °C with PEG. The observed pattern in K cat for G6P DH at high crowder concentrations has been explained via modelling using excluded volume theory. An increase in rate was observed at 45 °C for G6P DH versus 30 °C; this has been modelled via the Arrhenius equation.

BrEPS: a flexible and automatic protocol to compute enzyme-specific sequence profiles for functional annotation.

BackgroundModels for the simulation of metabolic networks require the accurate prediction of enzyme function. Based on a genomic sequence, enzymatic functions of gene products are today mainly predicted by sequence database searching and operon analysis. Other methods can support these techniques: We have developed an automatic method "BrEPS" that creates highly specific sequence patterns for the functional annotation of enzymes.ResultsThe enzymes in the UniprotKB are identified and their sequences compared against each other with BLAST. The enzymes are then clustered into a number of trees, where each tree node is associated with a set of EC-numbers. The enzyme sequences in the tree nodes are aligned with ClustalW. The conserved columns of the resulting multiple alignments are used to construct sequence patterns. In the last step, we verify the quality of the patterns by computing their specificity. Patterns with low specificity are omitted and recomputed further down in the tree. The final high-quality patterns can be used for functional annotation. We ran our protocol on a recent Swiss-Prot release and show statistics, as well as a comparison to PRIAM, a probabilistic method that is also specialized on the functional annotation of enzymes. We determine the amount of true positive annotations for five common microorganisms with data from BRENDA and AMENDA serving as standard of truth. BrEPS is almost on par with PRIAM, a fact which we discuss in the context of five manually investigated cases.ConclusionsOur protocol computes highly specific sequence patterns that can be used to support the functional annotation of enzymes. The main advantages of our method are that it is automatic and unsupervised, and quite fast once the patterns are evaluated. The results show that BrEPS can be a valuable addition to the reconstruction of metabolic networks.

Evolution under Fluctuating Environments Explains Observed Robustness in Metabolic Networks

A high level of robustness against gene deletion is observed in many organisms. However, it is still not clear which biochemical features underline this robustness and how these are acquired during evolution. One hypothesis, specific to metabolic networks, is that robustness emerges as a byproduct of selection for biomass production in different environments. To test this hypothesis we performed evolutionary simulations of metabolic networks under stable and fluctuating environments. We find that networks evolved under the latter scenario can better tolerate single gene deletion in specific environments. Such robustness is underlined by an increased number of independent fluxes and multifunctional enzymes in the evolved networks. Observed robustness in networks evolved under fluctuating environments was “apparent,” in the sense that it decreased significantly as we tested effects of gene deletions under all environments experienced during evolution. Furthermore, when we continued evolution of these networks under a stable environment, we found that any robustness they had acquired was completely lost. These findings provide evidence that evolution under fluctuating environments can account for the observed robustness in metabolic networks. Further, they suggest that organisms living under stable environments should display lower robustness in their metabolic networks, and that robustness should decrease upon switching to more stable environments.

Modeling and simulation of metabolic networks for estimation of biomass accumulation parameters

Metabolic networks are defined as the collection of biochemical reactions within a cell that define the functions of that cell. Due to the growing need to understand the functions of biological organisms for industrial and medical purposes, modeling and simulation of metabolic networks has attracted a lot of attention recently. Traditionally, metabolic networks are modeled such as flux-balance analysis that considers the steady state nature of the cell. However, it is important to consider the dynamic behavior of a cell since the environmental conditions change continuously. Sometimes due to the critical changes in the environment some of the reactions exhibit completely different behavior leading to discrete changes in the metabolic network. Therefore, a cell exhibits discrete-continuous behavior in continuous time. Since hybrid systems exhibit the same characteristics modeling a cell as a hybrid system gives an accurate representation. The aim of this paper is to develop a simulation framework to model the evolving structure of the cell metabolism under changes in the environment. The metabolic responses that cell gives, against multiple changes in the environment are not fully understood. Therefore, in this study, a cell is modeled as a hybrid system that is composed of a system of differential and algebraic equations. The changes in the concentration of metabolites in the environment are represented by Ordinary Differential Equations and the intracellular cell metabolism is represented by a set of algebraic equations. To understand the feedback relationship between intracellular and extracellular changes, the system is solved considering the effects of extracellular stresses on the metabolic responses.

Integration of metabolomics and proteomics in molecular plant physiology – coping with the complexity by data‐dimensionality reduction

In recent years, genomics has been extended to functional genomics. Toward the characterization of organisms or species on the genome level, changes on the metabolite and protein level have been shown to be essential to assign functions to genes and to describe the dynamic molecular phenotype. Gas chromatography (GC) and liquid chromatography coupled to mass spectrometry (GC- and LC-MS) are well suited for the fast and comprehensive analysis of ultracomplex metabolite samples. For the integration of metabolite profiles with quantitative protein profiles, a high throughput (HTP) shotgun proteomics approach using LC-MS and label-free quantification of unique proteins in a complex protein digest is described. Multivariate statistics are applied to examine sample pattern recognition based on data-dimensionality reduction and biomarker identification in plant systems biology. The integration of the data reveal multiple correlative biomarkers providing evidence for an increase of information in such holistic approaches. With computational simulation of metabolic networks and experimental measurements, it can be shown that biochemical regulation is reflected by metabolite network dynamics measured in a metabolomics approach. Examples in molecular plant physiology are presented to substantiate the integrative approach.

QPIPSA: relating enzymatic kinetic parameters and interaction fields.

BackgroundThe simulation of metabolic networks in quantitative systems biology requires the assignment of enzymatic kinetic parameters. Experimentally determined values are often not available and therefore computational methods to estimate these parameters are needed. It is possible to use the three-dimensional structure of an enzyme to perform simulations of a reaction and derive kinetic parameters. However, this is computationally demanding and requires detailed knowledge of the enzyme mechanism. We have therefore sought to develop a general, simple and computationally efficient procedure to relate protein structural information to enzymatic kinetic parameters that allows consistency between the kinetic and structural information to be checked and estimation of kinetic constants for structurally and mechanistically similar enzymes.ResultsWe describe qPIPSA: quantitative Protein Interaction Property Similarity Analysis. In this analysis, molecular interaction fields, for example, electrostatic potentials, are computed from the enzyme structures. Differences in molecular interaction fields between enzymes are then related to the ratios of their kinetic parameters. This procedure can be used to estimate unknown kinetic parameters when enzyme structural information is available and kinetic parameters have been measured for related enzymes or were obtained under different conditions. The detailed interaction of the enzyme with substrate or cofactors is not modeled and is assumed to be similar for all the proteins compared. The protein structure modeling protocol employed ensures that differences between models reflect genuine differences between the protein sequences, rather than random fluctuations in protein structure.ConclusionProvided that the experimental conditions and the protein structural models refer to the same protein state or conformation, correlations between interaction fields and kinetic parameters can be established for sets of related enzymes. Outliers may arise due to variation in the importance of different contributions to the kinetic parameters, such as protein stability and conformational changes. The qPIPSA approach can assist in the validation as well as estimation of kinetic parameters, and provide insights into enzyme mechanism.

Metabolic network simulation using logical loop algorithm and Jacobian matrix

A novel method to accomplish efficient numerical simulation of metabolic networks for flux analysis was developed. The only inputs required are the set of stoichiometric balances and the atom mapping matrices of all components of the reaction network. The latter are used to automatically calculate isotopomer mapping matrices. Using the symbolic toolbox of MATLAB the analytical solution of the stoichiometric balance equation system, isotopomer balances and the analytical Jacobian matrix of the total set of stoichiometric and isotopomer balances are created automatically. The number of variables in the isotopomer distribution equation system is significantly reduced applying modified isotopomer mapping matrices. These allow lumping of several consecutive isotopomer reactions into a single one. The solution of the complete system of equations is improved by implementing an iterative logical loop algorithm and using the analytical Jacobian matrix. This new method provided quick and robust convergence to the root of such equation systems in all cases tested. The method was applied to a network of lysine producing Corynebacterium glutamicum. The resulting equation system with the dimension of 546×546 was directly derived from 12 isotopomer balance equations. The results obtained yielded identical labeling patterns for metabolites as compared to the relaxation method.

SCAMP: A metabolic simulator and control analysis program

Previously developed metabolic simulation programs have concentrated on providing the facility to make time-dependent simulations of metabolic networks; few have been concerned with the steady state and even fewer with any steady state analysis, in particular metabolic control analysis. Here we describe a new simulation program SCAMP, which includes the facility to make time-dependent simulations, but in addition incorporates many of the concepts of metabolic control analysis. SCAMP makes available all the coefficients defined in the control analysis of Kacser and Burns [1] and Heinrich and Rapoport [2]. Thus control coefficients, response coefficients (including the conserved cycle coefficients defined by Hofmeyr et al. [3]) and elasticities (including kappa and pi elasticities [4]) can all be calculated easily. Two other special facilities have also been incorporated; conserved cycle identification and the inclusion of a simple data base of enzyme rate laws. SCAMP will accept models in terms of mass action reactions, user-defined (or data base-defined) rate law reactions or differential equations. SCAMP was primarily implemented for the Atari ST microcomputer since the ST supports a large continuous memory map. However, it is possible to run SCAMP on an MS-DOS type microcomputer provided there is at least 640K of memory. We also supply a simple command shell which integrates the various parts for both the Atari and MS-DOS version. The Atari version also includes a useful graphics plotting package.