02inov12n1

02inov12n1 - Harvard-MIT Division of Health Sciences and...

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Harvard-MIT Division of Health Sciences and Technology HST.508: Genomics and Computational Biology Protein2: Last week's take home lessons • Separation of proteins & peptides • Protein localization & complexes • Peptide identification (MS/MS) – Database searching & sequencing. • Protein quantitation – Absolute & relative • Protein modifications & crosslinking • Protein - metabolite quantitation 1
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Net1: Today's story & goals Macroscopic continuous concentration rates Cooperativity & Hill coefficients Bistability Mesoscopic discrete molecular numbers Approximate & exact stochastic Chromosome Copy Number Control Flux balance optimization Universal stoichiometric matrix Genomic sequence comparisons 2
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Networks Why model? Red blood cell metabolism Enzyme kinetics (Pro2) Cell division cycle Checkpoints (RNA2) Plasmid Copy No. Control Single molecules Phage λ switch Stochastic bistability Comparative metabolism Genomic connections Circadian rhythm Long time delays E. coli chemotaxis Adaptive, spatial effects also, all have large genetic & kinetic datasets. 3
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Types of interaction models Quantum Electrodynamics Quantum mechanics Molecular mechanics Master equations Phenomenological rates ODE Flux Balance Thermodynamic models Steady State Metabolic Control Analysis Spatially inhomogenous models subatomic electron clouds spherical atoms (101Pro1) stochastic single molecules (Net1) Concentration & time (C,t) dC ik /dt optima steady state (Net1) dC ik /dt = 0 k reversible reactions Σ dC ik /dt = 0 (sum k reactions) d(dC ik /dt)/dC j (i = chem.species) dCi/dx Increasing scope, decreasing resolution 4
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In vivo & (classical) in vitro 1) "Most measurements in enzyme kinetics are based on initial rate measurements, where only the substrate is present… enzymes in cells operate in the presence of their products" Fell p.54 (Pub) (http://www.amazon.com/exec/obidos/ASIN/185578047X/) 2) Enzymes & substrates are closer to equimolar than in classical in vitro experiments. 3) Proteins close to crystalline densities so some reactions occur faster while some normally spontaneous reactions become undetectably slow. e.g. Bouffard, et al., Dependence of lactose metabolism upon mutarotase encoded in the gal operon in E.coli. J Mol Biol. 1994; 244:269-78. (Pub) (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7966338&dopt=Abstract) 5
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Human Red Blood Cell ODE model LAC e GLC e Na + ODE model Jamshidi et al.2000 (Pub) GLC i G6P F6P FDP GA3P DHAP 1,3 2,3 PEP PYR LAC i GL6P GO6P X5P GA3P S7P F6P E4P GA3P NADP NADPH NADP NADPH ADP ATP ADP ATP ADP ATP NADH NAD ADP ATP NADH NAD K + ADP ATP ADP ATP 2 NADPH NADP ADO INO AMP IMP ADO e INO e ADE ADE e HYPX PRPP PRPP ATP AMP ATP ADP Cl - pH HCO 3 - DPG DPG 3PG 2PG RU5P R5P F6P GSH GSSG R1P R5P (http://atlas.med.harvard.edu/gmc/rbc.html) 6
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Factors Constraining Metabolic Function • Physicochemical factors – Mass, energy, and redox balance: • Systemic stoichiometry – osmotic pressure, electroneutrality, solvent capacity, molecular diffusion, thermodynamics – Non-adjustable constraints
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02inov12n1 - Harvard-MIT Division of Health Sciences and...

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