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Welcome to Integrated Bioinformatics Friday, 18 November 2016 Metabolic Modeling Welcome to Integrated Bioinformatics Friday, 18 November 2016 Metabolic Modeling Welcome to Integrated Bioinformatics Friday, 18 November 2016 Metabolic Modeling What to do today, tomorrow,...? I would like to work in industry . My career goal is to be a part of a health care organization Industrial analysis work I would like some return on my educational investment…working as bioinformatican or as a scientific software engineer. [From a graduate now in industry] [From a graduate now in industry] I’ve been working in the biotech industry as a Bioinformaticist for 2 years. In that time frame I’ve learned many things school didn’t and probably couldn’t teach me... What I didn’t know was how to ... Develop an automated downstream analysis for... how to... how to.... Without guidance except my brain and my intuition... I was able to pull this stunt off. I can honestly say I know a lot and yet I feel like I know nothing, but typically I do know where I can find the answer... My goals for this module 1. Provide you an opportunity to figure out solutions to problems outside of your experience My goals for this module 1. Provide you an opportunity to figure out solutions to problems outside of your experience 2. Metabolism has logic My goals for this module 1. Provide you an opportunity to figure out solutions to problems outside of your experience 2. Metabolism has logic 3. Metabolism can be modeled mathematically My goals for this module 1. Provide you an opportunity to figure out solutions to problems outside of your experience 2. Metabolism has logic 3. Metabolism can be modeled mathematically 4. Problems can be modeled computationally My goals for this module 1. Provide you an opportunity to figure out solutions to problems outside of your experience 2. Metabolism has logic 3. Metabolism can be modeled mathematically 4. Problems can be modeled computationally 5. Models can tell you when your understanding is faulty My goals for this module 1. Provide you an opportunity to figure out solutions to problems outside of your experience 2. Metabolism has logic 3. Metabolism can be modeled mathematically 4. Problems can be modeled computationally 5. Models can tell you when your understanding is faulty No, I am so confused. Please help! Sample Question • General frame I’m confused about the coordinate system. Sample Question • General frame • Specific frame I’m confused about the coordinate system. Sample Question • General frame • Specific frame I’m confused about the coordinate system. Specifically, I don’t understand how to use the numbers near genes to find their sequences. Sample Question • General frame • Specific frame • Specific example I’m confused about the coordinate system. Specifically, I don’t understand how to use the numbers near genes to find their sequences. Sample Question • General frame • Specific frame • Specific example I’m confused about the coordinate system. Specifically, I don’t understand how to use the numbers near genes to find their sequences. I tried with the first number for Ava0001 (119), but that number doesn’t exist amongst the coordinates shown. Sample Question • General frame • Specific frame • Specific example • Attempt to resolve I’m confused about the coordinate system. Specifically, I don’t understand how to use the numbers near genes to find their sequences. I tried with the first number for Ava0001 (119), but that number doesn’t exist amongst the coordinates shown. Sample Question • General frame • Specific frame • Specific example • Attempt to resolve I’m confused about the coordinate system. Specifically, I don’t understand how to use the numbers near genes to find their sequences. I tried with the first number for Ava0001 (119), but that number doesn’t exist amongst the coordinates shown. I tried counting from coordinate 1 but that led me to the letters GAT when I believe the gene should begin ATG. Sample Question • General frame • Specific frame • Specific example • Attempt to resolve • Optional rant I’m confused about the coordinate system. Specifically, I don’t understand how to use the numbers near genes to find their sequences. I tried with the first number for Ava0001 (119), but that number doesn’t exist amongst the coordinates shown. I tried counting from coordinate 1 but that led me to the letters GAT when I believe the gene should begin ATG. Sample Question • General frame • Specific frame • Specific example • Attempt to resolve • Optional rant I’m confused about the coordinate system. Specifically, I don’t understand how to use the numbers near genes to find their sequences. I tried with the first number for Ava0001 (119), but that number doesn’t exist amongst the coordinates shown. I tried counting from coordinate 1 but that led me to the letters GAT when I believe the gene should begin ATG. What kind of idiot would invent such a nonintuitive system?!?!? Sample Question • General frame • Specific frame • Specific example • Attempt to resolve • Optional rant • Specific request I’m confused about the coordinate system. Specifically, I don’t understand how to use the numbers near genes to find their sequences. I tried with the first number for Ava0001 (119), but that number doesn’t exist amongst the coordinates shown. I tried counting from coordinate 1 but that led me to the letters GAT when I believe the gene should begin ATG. What kind of idiot would invent such a nonintuitive system?!?!? Sample Question • General frame • Specific frame • Specific example • Attempt to resolve • Optional rant • Specific request I’m confused about the coordinate system. Specifically, I don’t understand how to use the numbers near genes to find their sequences. I tried with the first number for Ava0001 (119), but that number doesn’t exist amongst the coordinates shown. I tried counting from coordinate 1 but that led me to the letters GAT when I believe the gene should begin ATG. What kind of idiot would invent such a nonintuitive system?!?!? I wonder if you could give some insight as to why my experiment failed. Sample Question • General frame • Specific frame • Specific example • Attempt to resolve • Optional rant • Specific request • Polite closing I’m confused about the coordinate system. Specifically, I don’t understand how to use the numbers near genes to find their sequences. I tried with the first number for Ava0001 (119), but that number doesn’t exist amongst the coordinates shown. I tried counting from coordinate 1 but that led me to the letters GAT when I believe the gene should begin ATG. What kind of idiot would invent such a nonintuitive system?!?!? I wonder if you could give some insight as to why my experiment failed. Thanks. Why Metabolic Modeling Rational drug design Trypanosoma brucei Causative agent of sleeping sickness Life Cycle Central Nervous System Death Trypanosoma brucei How to stop it? Standard antibiotic targets Cell wall e.g. penicillins Bacterial ribosomes e.g. neomycin Bacterial RNA polymerase e.g. rifampicin Bacterial DNA gyrase e.g. nalidixic acid Trypanosomes have eukaryotic machinery, like us Trypanosoma brucei How to stop it? Them ATP Glucose Us Glycolysis Glycolysis Pyruvate Pyruvate Citric Acid Cycle ATP ATP Trypanosoma brucei How to stop it? Glucose Them ATP Us Glycolysis Glycolysis Pyruvate Pyruvate Citric Acid Cycle ATP ATP Alternative to exhaustive lab testing Glycolysis Symbolically Glucose Hexokinase Glucose-6-P + ATP + ADP Mathematically dG6P/dt = kf [Glc][ATP] Computationally dG6P.dxdt = kf*glc*atp … exhaustive computational modeling Alternative to exhaustive lab testing Glycolysis dGlc/dt = +kf1 [Glcx] -kr2[Glc] -kf2[Glc][ATP] dG6P/dt = +kf2 [Glc][ATP] -kf3[G6P] dF6P/dt = +kf3 [G6P]-kr3[F6P] -kf4[F6P][AT] dFDP/dt = +kf4 [F6P][ATP]-kf5[FDP] dDHAP/dt = +kf5 [FDP]+kr6[G3P] -kf6[DHAP] dG3P/dt = +kf5 [FDP]+kf6[DHAP] -kr6[G3P] -kf7[G3P][NAD]+kry[13PGA][NADH] d13PGA/dt = kf7[G3P][NAD]-kry[13PGA][NADH] -kf8[13PGA][ADP]+kr8[3PGA][ATP] ... inhibitor1 Alternative to exhaustive lab testing Everything dGlc/dt = +kf1 [Glcx] -kr2[Glc] -kf2[Glc][ATP] dG6P/dt = +kf2 [Glc][ATP] -kf3[G6P] dF6P/dt = +kf3 [G6P]-kr3[F6P] -kf4[F6P][AT] dFDP/dt = +kf4 [F6P][ATP]-kf5[FDP] dDHAP/dt = +kf5 [FDP]+kr6[G3P] -kf6[DHAP] dG3P/dt = +kf5 [FDP]+kf6[DHAP] -kr6[G3P] -kf7[G3P][NAD]+kry[13PGA][NADH] d13PGA/dt = kf7[G3P][NAD]-kry[13PGA][NADH] -kf8[13PGA][ADP]+kr8[3PGA][ATP] ... My goals for this module 1. Provide you an opportunity to figure out solutions to problems outside of your experience 2. Metabolism has logic 3. Metabolism can be modeled mathematically 4. Problems can be modeled computationally 5. Models can tell you when your understanding is faulty What is glycolysis Glucose Pyruvate ATP How do I get to my hotel? Airport Hotel $$$ What is glycolysis Glucose Pyruvate ATP What is glycolysis Glucose Pyruvate ATP What is glycolysis Glucose Pyruvate ATP What is glycolysis glucose HO OH OH OH O OH OO ATP + OH pyruvate What is glycolysis glucose OH HO OH OH HO methanol O OH OH OH OH O OH OO ATP + OH pyruvate What is glycolysis glucose HO OH OH OH O OH OH OH OH OH O OH OH OH O OH OO ATP + OH pyruvate What is glycolysis glucose HO OH OH O OH OH OH OH OH O OH OH OH O OH OH O OH OH OO ATP + OH pyruvate What is glycolysis glucose HO OH OH OH blood cell O OH OO ATP + OH pyruvate What is glycolysis glucose HO OH OH OH O permease OH blood cell OO OH pyruvate What is glycolysis glucose HO permease OH OH OH blood cell OO OH pyruvate O OH What is glycolysis glucose HO OH OH OH O permease OH ATP blood cell O O O O-P-O O-P-O O-P-O -Adenosine O O O Anhydride (acid + acid) 2 OO OH pyruvate What is glycolysis glucose HO permease OH OH OH O OH ATP blood cell O O O O-P-O O-P-O O-P-O -Adenosine O O O Anhydride (acid + acid) 2 OO OH pyruvate What is glycolysis O glucose O-P-O O permease OH OH OH O OH ADP blood cell O O O-P-O O-P-O -Adenosine O O Anhydride (acid + acid) 2 OO OH pyruvate What is glycolysis glucose O permease OH OH OH O OH ADP blood cell O O O-P-O O-P-O -Adenosine O O Anhydride (acid + acid) 2 OO OH pyruvate What is glycolysis ATP ADP glucose HO OH OH OH O glucose-6P OH O OH O OH OH OH Hexokinase Ketone or aldehyde O ??? O 2 ATP + 2 OO OH pyruvate Enol What is glycolysis ATP ADP glucose HO OH OH OH O glucose-6P OH O OH O OH OH O OH ??? 2 ATP + 2 OH pyruvate OHO OH Hexokinase OO OH OH What is glycolysis ATP ADP glucose HO OH OH OH O glucose-6P OH O OH O OH OH O OH OH Hexose-P isomerase Hexokinase OO 2 ATP + 2 fructose-6P OH pyruvate OHO OH O OH OH OHO OH OH What is glycolysis ATP ADP glucose HO OH OH OH O ATP ADP glucose-6P OH O OH O OH OH O OH OH Hexose-P isomerase Hexokinase OO 2 ATP + 2 fructose-6P OH pyruvate OHO OH fructose-1,6 diP O OH Phospho fructokinase OH OHO OH O What is glycolysis ATP ADP glucose HO OH OH OH O ATP ADP glucose-6P OH O OH O OH OH fructose-6P O OH OH Hexose-P isomerase Hexokinase OHO OH fructose-1,6 diP O OH OHO OH OH O Phospho fructokinase Aldolase O OH O glyceraldehyde 3-P (Gla3P) 2 ATP + 2 OO OH pyruvate OHO O Dihydroxy acetone P (DHAP) What is glycolysis ATP ADP glucose HO OH OH OH O ATP ADP glucose-6P OH O OH O OH OH fructose-6P O OH OH Hexose-P isomerase Hexokinase OHO OH fructose-1,6 diP O OH OHO OH OH O Phospho fructokinase Aldolase Triose P isomerase 2 ATP + 2 OO OH pyruvate O OH O Gla3P OHO O DHAP What is glycolysis ATP ADP glucose HO OH OH OH O ATP ADP glucose-6P OH O OH O OH OH fructose-6P O OH Hexose-P isomerase fructose-1,6 diP O OH OH OH Hexokinase OHO OHO OH O OH Phospho fructokinase Aldolase Triose P isomerase O OHO OH O O Gla3P DHAP NAD+ O 2 ATP + 2 OO OH pyruvate NADH Gla 3-P dehydrogenase O OH O O O ADP ATP OH O O 3-P-glycerate (3PG) What is glycolysis ATP ADP glucose HO OH OH OH ATP ADP glucose-6P O O OH OH OH OH fructose-6P O OH OO OH pyruvate OHO fructose-1,6 diP O OH OH OH Hexose-P isomerase Hexokinase 2 ATP + 2 O OHO OH O OH Phospho fructokinase Aldolase Triose P isomerase O OHO OH O O Gla3P DHAP NAD+ O NADH Gla 3-P dehydrogenase O OH O O O ADP ATP OH O O 3-P-glycerate (3PG) What is glycolysis ATP ADP glucose HO OH OH OH ATP ADP glucose-6P O OH O OH OH OH fructose-6P O OH OO OH pyruvate OHO fructose-1,6 diP O OH OH OH Hexose-P isomerase Hexokinase 2 ATP + 2 O OHO OH O OH Phospho fructokinase Aldolase Triose P isomerase O OHO OH O O Gla3P DHAP NAD+ O O O O OH O NADH Gla 3-P dehydrogenase O O O 2-P-glycerate (3PG) ADP ATP OH O O O O OH O 3-P-glycerate (3PG) Trypanosoma brucei How to exploit dependence on glycolysis? blood cell Treatment Arsenate (AsO4 = Asi) Periodic Table Trypanosoma brucei How to exploit dependence on glycolysis? blood cell Treatment Arsenate (AsO4 = Asi) Competitive with Pi Trypanosoma brucei How to exploit dependence on glycolysis? Glyceraldehyde-3-P NAD+ O O O-P-O-CH2—CH—C H O NADH ADP O O O O-P-O-CH2—CH—C- O-P-O O O ATP 3-P-Glycerate O O O-P-O-CH2—CH—C-O O O O-P-O O Trypanosoma brucei How to exploit dependence on glycolysis? Glyceraldehyde-3-P NAD+ O O-As-O O O O O-P-O-CH2—CH—C H O H2O NADH O O O O-P-O-CH2—CH—C- O-As-O O O ADP ATP 3-P-Glycerate O O O-P-O-CH2—CH—C-O O + O O-As-O O Trypanosoma brucei How to exploit dependence on glycolysis? Glyceraldehyde-3-P O ADP- O-As-O O NAD+ O O O-P-O-CH2—CH—C H O H2O NADH O O O O-P-O-CH2—CH—C- O-As-O O O ADP O ADP + O-As-O ATP O 3-P-Glycerate O O-As-O O O O O-P-O-CH2—CH—C-O O + O O-As-O O My goals for this module 1. Provide you an opportunity to figure out solutions to problems outside of your experience 2. Metabolism has logic 3. Metabolism can be modeled mathematically 4. Problems can be modeled computationally 5. Models can tell you when your understanding is faulty How to model this reaction? (Spontaneous) 1 [S] 0.8 0.6 0.4 0.2 0 0 1 2 3 t (sec) 4 5 How to model this reaction? (Spontaneous) velocity? ADP-As ADP +Asi [ADP-As] concentration k = d[ADP] / dt rate constant rate of change d[Asi] / dt rate of change – d[ADP-Asi] / dt rate of change k [S] = – d[Si] / dt How to model this reaction? (Spontaneous) velocity? ADP-As A differential equation Its solution? ADP +Asi = d[S] / dt = –k[S] [S] = How to model this reaction? (Spontaneous) velocity? ADP-As A differential equation Its solution? Check: ADP +Asi = d[S] / dt = –k[S] [S] = S0 e -k(t-to) = d[S] / dt = S0 (–k) e -k(t-to) = -k S0 e -k(t-to) = -k [S] How to model this reaction? (Spontaneous) 1 [S] 0.8 [S] = S0 e -k(t-to) 0.6 0.4 0.2 0 0 1 2 3 t (sec) 4 5 How to model this reaction? (Spontaneous) How to model this reaction? (Spontaneous) 1 If you know the slope… [S] 0.8 (Do you?) 0.6 0.4 = d[S] / dt = –k[S] 0.2 0 0 1 2 3 t (sec) 4 5 My goals for this module 1. Provide you an opportunity to figure out solutions to problems outside of your experience 2. Metabolism has logic 3. Metabolism can be modeled mathematically 4. Problems can be modeled computationally 5. Models can tell you when your understanding is faulty How to model this reaction? (Spontaneous) How to model this reaction? (Spontaneous) 1 S0 [S] = S0 + Δt d[S] / dt [S] 0.8 0.6 Δt 0.4 = d[S] / dt = –k[S] 0.2 0 0 1 2 3 t (sec) 4 5 How to model this reaction? (Spontaneous) 1 [S] = S0 + Δt d[S] / dt [S] 0.8 SQ3. Why is it that the predicted levels are all lower than the calculated levels? S0 0.6 0.4 Δt = d[S] / dt = –k[S] 0.2 0 0 1 2 3 t (sec) 4 5 How to model this reaction? (Spontaneous) 1 [S] = S0 + Δt d[S] / dt [S] 0.8 SQ4. Modify the two programs to make S0 produce numbers that bring the two curves closer together. Δt What’s key trick? = d[S] / dt the = –k[S] 0.6 0.4 0.2 0 0 1 2 3 t (sec) 4 5 My goals for this module 1. Provide you an opportunity to figure out solutions to problems outside of your experience Enymatically catalyzed 2. Metabolism has logic V 3. Metabolism can be modeled mathematically 4. Problems can be modeled computationally 5. Models can tell you when your understanding is faulty How to model this reaction? (Catalyzed) How to model this reaction? (Catalyzed) What is the rate equation? Glucose-6-phosphate [G6P] concentration Fructose-6-phosphate k = = d[F6P] / dt rate constant ??? k~0 rate of change Characteristics of enzymes Enzymatic reactions Characteristics of enzymes Enzymatic reactions G6P + E G6P·E F6P·E E-complex F6P + E How to model this reaction? (Catalyzed) G6P + E G6P·E F6P·E E-complex = d[G6PE] / dt = F6P + E How to model this reaction? (Catalyzed) How to model this reaction? (Catalyzed) What are the units of kf and kr? How to model this reaction? (Catalyzed) G6P + E G6P·E F6P·E F6P + E E-complex = d[G6PE] / dt = = d[F6P] / dt = Rates of changes of metabolites Rates of changes of metabolites SQ5. Write an expression that gives the concentration of F6P at time t + dt. Spontaneous vs Catalyzed Metabolic Modeling Metabolic Modeling Metabolic Modeling