Presentation on theme: "Computer modeling of cellular processes"— Presentation transcript:
1 Computer modeling of cellular processes Glycolysis: a few reactionsByRaquell M. Holmes, Ph.D.Boston University
2 Dynamics: Answering different questions If glucose concentration is 300 mM outside of the cell,How quickly is glucose converted to glucose 6-phosphate?How does the concentration of glucose 6 phosphate change over time?
3 Yeast Glycolysis suspended immobile Liquid, flasks, temp, ph Experiment:Sample media or characterize cell content over timeRepeat under different conditionsimmobileAgar, temp, ph
5 Computer ModelingMethod for analyzing what we know about a biological processUsed to describe mechanisms behind changesDetermines what can be seen or predicted
6 Walking through a Computational Model Concept MapFactors and relationships between factorsDescribe relationships mathematicallySolve equations: using computer toolsView and interpret results
7 Designing a dynamic experiment What components are involved?Glucose, glucose 6 phosphate, fructose 6 phosphate…What chemical reactions involved?Transport, chemical conversions…
8 Glycolysis: Concept Map Often drawings, schematics or chemical reactionsv1v2v3v4Glucose6-phosphateFructose6-phosphateGlucoseInternalGlucoseEthanolCell
9 Examples of relationships Glucose6-phosphateFructosev1v2InternalGlucose[Glucose 6-phosphate] is determined by increase from Glucose conversion and decrease by conversion to Fructose 6-phosphateAmount of glucose 6 phosphate= amount produced- amount converted
10 Designing a dynamic experiment Describing relationship mathematically
11 Relationship in terms of rates of change The rate of change of Glucose-6-phosphate (S2) is the rate of Glucose conversion (v1) minusthe rate of conversion (v2) to Fructose-6-phosphate.
12 Designing a dynamic experiment Describing relationship mathematicallyWhat rate laws are known to describe the enzymatic reaction?Types of rate laws/kinetic modelsConstant, mass action, michaelis menten…
13 SimplifyGlucose transport (v1)Facilitated diffusion
14 Rate Equations Substrates Glucose: Glucose- 6-phosphate: Rate constantsEnzyme1:Enzyme2:Mass action kinetics are used here to describe the enzymatic reactions.This is a simplification of the enzyme kinetics for this example.
15 Initial conditions Concentrations of components Enzymatic rates External glucose (i.e. 300mM)Enzymatic ratesRate constant k (i.e. 50mM/min)Michaelis-Menten constants, Hill Coefficients
16 The model Glucose 6-phosphate Fructose v1 v2 Internal S1=300mM Ordinary differential equationRate equationsInitial conditionsS1=300mMk1=55mM/mink2=9.8mM/min
17 Walking through a Computational Model Concept MapFactors and relationships between factorsDescribe relationships mathematicallySolve equations: using computer toolsView and interpret results
18 Some Available Tools General Stella InstallMac or PCExcelCustomizedGEPASIVirtual CellBrowser: JavaConcept mapping and system dynamics (changes over time).Discrete events, algebraic equationsBiochemical kinetics and kinetic analyses.Icon mapping, dynamics and space
19 StellaConcept MapRules as mathInitial Conditions
23 Conclusions… Model based discoveries in glycolysis:: Oscillations in concentrations of some but not all metabolites.Control of process distributed throughout pathwayDevelopment of theoretical modelsMethod integrates knowledge of pathway factors to examine pathway behaviors.
24 Examples of other models Calcium dynamics: Wave patterns in neuronal cellsVirtual CellReceptor signaling: IgE triggering mast cellsPersonal computer codesCell cycle regulation: length of wee 1 mutant cell divisionsMatlab, Mathematica, personal computer codes
27 Modeling Requires formalizing assumptions Worst case scenario Rate equationsInclusion or exclusion from modelWorst case scenarioSee what you believeBest case scenarioSee something unexplainableCreate new laboratory experiments