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**Simulation Programs: What is out there? A critical**evaluation. Prof:Rui Alves ralves@cmb.udl.es 973702406 Dept Ciencies Mediques Basiques, 1st Floor, Room 1.08 Website of the Course:http://web.udl.es/usuaris/pg193845/Courses/Bioinformatics_2007/ Course: http://10.100.14.36/Student_Server/**Simulation is becoming widespread**• Kinetic models are becoming a common tool for testing biological hypothesis. • A plethora of different software packages for model building, simulation and analysis is available. • How far are we from having reliable tools that make simulation accessible to non-expert mathematical modelers? • What tools are more adequate for different types of problems?**Addressing the questions**• Choose representative simulation packages. • Identify features in each of them. • Test how accurately these features work. • Evaluate how much expertise one needs to use each program.**Emphasis**• Simulators • Type of input • Models used for testing • Analytical capabilities of the software • Cross-compatibility between the software • What to use for each type of problem**Rationale for excluding software**• Kinetic Modeling Packages that require expert knowledge about the mother-software excluded • Not for non-experts + expensive • Commercial user-friendly simulation software provides no new functionality with respect to free software. Also, we could not get temporary evaluation licenses for some of them, so we excluded them all.**Evaluated Simulation Packages**• Kinetic Modeling Packages • Excludes software that implement functionality in a pre-existing software platform (e.g. BST lab in MATLAB). • Free Stand alone simulators • Excludes e.g. STELLA and MADONNA • Free Internet Simulation Servers • Free Network editors**Rationale for choices of models**• Models that allowed the testing of the different features. • In some cases model with analytical solutions so that accuracy of calculations could be determined**Models used in the evaluation (1)**• Escherichia coli’s phosphoenolpyruvate:glucose phosphotransferase system (mass action; 1 compartment) • GAL4 system of Saccharomyces cerevisiae (mass action; 1 compartment) Tests for stochastic simulators**Models used in the evaluation (2)**Source reactions Reactions with modifiers Reactions with catalysts Homo molecular reactions**Models used in the evaluation (3)**• Simple difusion two compartment model**Models used in the evaluation (4)**• Simple two reaction model with analytical solution to evaluate sensitivity and stability analysis X1 X2 Tests for stability and sensitivity analysis as well as moiety conservation calculations**Analytical capabilities of the software**Incorrect for models with moiety conservation Incorrectly implemented jacobian calculations**Compartmental model implementation model 4**Write all equations/Draw diagrams Choose Kinetic equations/Write KEs Interface reaction parameters must be correct to have the appropriate units Permeability constant converted into apparent rate constants Kinetic parameters multiplied by volume of corresponding compartment**Exceptions:**V-Cell Dizzy – Convert everything into ammounts rather than concentrations Cellware – Chose a reference compartment and convert all concentrations to that compartment**Crosstalk between software**• It is important to be able to share models between different software programs • SBML is becoming the standard**Trouble in SBMLland**• reaction stoichiometries defined as floating point values; • boundary metabolites; • source reactions • sink reactions • reactions where the stoichiometry for one of reactants or products is larger than 1; • kinetic type definitions can prevent correct interpretation of models by stochastic simulators. • Definition of compartments breaks down for variable volumes**There is hope in SBMLand**• A small amount of editing is in general sufficient to correct imcompatible SBML models • A redefinition of comparments is straightforward**Goals of the model (I)**• Large scale modeling • Reconstructing the full network of the genome • Red Blood Cell Metabolism • Dialog or diagram based, with possibility for modular implementation • COPASI, GEPASI, V-CELL, CELLDESIGNER,JDESIGNER • Sensitivity analysis • COPASI, GEPASI, jdesigner, v-cell**Goals of the model (I)**• Modeling Specific Pathways/Circuits • Non-catalytic lipid peroxidation • MAPK Pathways • Any type of input; • Sensitivity analysis • COPASI, GEPASI, jdesigner, PLAS, v-cell, celldesigner**Goals of the model (I)**• Generating alternative hypothesys for the topology of the model. • Must allow for structured functional forms and for large scale parameter scans • COPASI, GEPASI, jdesigner, PLAS, celldesigner**Goals of the model (II)**• Estimating parameter values • Must have fitting algorithms • COPASI, GEPASI,DYNAFIT • Identifying Design Principles • None, so far; howver we have a MATHEMATICA package that allows you to do this.**Final Conclusion**• Our analysis has convinced us that a non-trivial degree of expertise is still required for the use of simulation programs to create models. • It is dangerous to expect that a non-expert will create a useful and correct model of a biological process. Alves et al. Nature Biotechnology 2006