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LSM3241: Bioinformatics and Biocomputing Lecture 9: Biological Pathway Simulation Prof. Chen Yu Zong Tel: 6874-6877 Email: [email protected] http://xin.cz3.nus.edu.sg Room 07-24, level 7, SOC1, NUS. Biomolecular Interaction: Enzyme + Substrate. - PowerPoint PPT Presentation
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LSM3241: Bioinformatics and BiocomputingLSM3241: Bioinformatics and Biocomputing
Lecture 9: Biological Pathway Simulation Lecture 9: Biological Pathway Simulation
Prof. Chen Yu ZongProf. Chen Yu Zong
Tel: 6874-6877Tel: 6874-6877Email: Email: [email protected]@cz3.nus.edu.sg
http://xin.cz3.nus.edu.sghttp://xin.cz3.nus.edu.sgRoom 07-24, level 7, SOC1, NUSRoom 07-24, level 7, SOC1, NUS
22
Biomolecular Interaction: Enzyme + SubstrateBiomolecular Interaction: Enzyme + Substrate
E + S ==> E + P
• This is a generalization of how a biochemist might represent the function of enzymes.
33
Biomolecular Interaction: Enzyme + SubstrateBiomolecular Interaction: Enzyme + Substrate
E + S ==> E + P
kinase-ATP complex + inactive-enzyme ==> Kinase + ADP + active enzyme
K
ATP ADP
P
• Here is an example of the generalization represented by two different ways.
44
Biomolecular Interaction: Enzyme + SubstrateBiomolecular Interaction: Enzyme + Substrate
• This is another representation.
Kinase-ATPcomplex
Activeenzyme
inactiveenzyme
ADP
55
Spoke and Matrix Models of Protein-Spoke and Matrix Models of Protein-Protein InteractionsProtein Interactions
Vrp1 (bait), Las17, Rad51, Sla1, Tfp1, Ypt7
SpokeMatrixPossible Actual
Topology
Bader&Hogue Nature Biotech. 2002 Oct 20(10):991-7
Simple model
Intuitive, more accurate, but canmisrepresent
Theoretical max. no. of interactions, but many FPs
66
Synthetic Genetic Interactions in Yeast
Tong, Boone
Cell PolarityCell Wall Maintenance Cell StructureMitosisChromosome StructureDNA Synthesis DNA RepairUnknownOthers
77
• Glycolysis– Phosphorylation– Pyruvate
• Anaerobic respiration• Lactate production• 2 ATPs produced
Metabolic Pathway: ATP ProductionMetabolic Pathway: ATP Production
88
Cyclic Metabolic Pathway
99
Methods of Metabolic Engineering
1010
Generic Signaling PathwayGeneric Signaling PathwaySignal
Receptor (sensor)
Transduction Cascade
Targets
Response Altered
Metabolism
MetabolicEnzyme
Gene Regulator Cytoskeletal Protein
Altered Gene
Expression
Altered Cell Shape or Motility
1111
Components of SignalingWhat can be the Signal?External message to the cell
• Peptides / Proteins- Growth Factors• Amino acid derivatives - epinephrine, histamine• Other small biomolecules - ATP• Steroids, prostaglandins• Gases - Nitric Oxide (NO)• Photons• Damaged DNA• Odorants, tastants
Signal = LIGANDLigand- A molecule that binds to a specific site on another molecule, usually a protein, ie receptor
1212
Components of SignalingWhat are Receptors?Sensors, what the signal/ligand binds to initiate ST
Cell surface
Intracellular
Hydrophillic LigandCell-Surface Receptor
Plasma membrane
Hydrophobic Ligand
Carrier Protein
IntracellularReceptor
Nucleus
1313
Generic Signal Transduction
1414
RTK Signal Transduction
1515
Signal TransductionDownstream effectors
Protein Signaling Modules (Domains)
SH2 and PTB bind to tyrosine phosphorylated sitesSH3 and WW bind to proline-rich sequencesPDZ domains bind to hydrophobic residues at the C-termini of target proteinsPH domains bind to different phosphoinositidesFYVE domains specifically bind to Pdtlns(3)P (phosphatidylinositol 3-phosphate)
1616
Mechanisms for Activation of Signaling Proteins by RTKs
Activation by membrane translocation
Activation by a conformational change
Activation by tyrosine phosphorylation
1717
Mechanisms for Attenuation & Termination of RTK Activation
1) Ligand antagonists2) Receptor antagonists3) Phosphorylation and dephosphorylation4) Receptor endocytosis5) Receptor degradation by the ubiquitin-proteosome pathway
1818
Activation of MAPK Pathways by Multiple Signals
Growth, differentiation, inflammation, apoptosis -> tumorigenesis
1919
Overview of MAPK Signaling Pathways
2020
The MAPK Pathway Activated by RTK
2121
RTK ST- PI3K pathway
P
2222
Apoptosis Pathways
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TGF Pathway
2424
Constructing a pathway model:Constructing a pathway model:things to considerthings to consider
1. Dynamic nature of biological networks.Biological pathway is more than a topological linkage of molecular networks.
Pathway models can be based on network characteristics including those of invariant features.
2525
Constructing a pathway model:Constructing a pathway model:things to considerthings to consider
2. Abstraction Resolution:
• How much do we get into details?
• What building blocks do we use to describe the network?
High resolution
Low resolution
(A) Substrates and proteins
(B) Pathways
(C) “special pathways”
2626
Constructing a pathway modelConstructing a pathway modelStep I - DefinitionsStep I - Definitions
We begin with a very simple imaginary metabolic network represented as a directed graph:
Vertex – protein/substrate concentration.
Edge - flux (conversion mediated by proteins of one substrate into the other)
Internal flux edge
External flux edge
How do we define a
biologically significant
system boundary?
Constructing a pathway modelConstructing a pathway modelStep II: Interaction KineticsStep II: Interaction Kinetics
E + S ==> E + P
kinase-ATP complex + inactive-enzyme ==> Kinase + ADP + active enzyme
K
ATP ADP
P
2828
Reversibility of Chemical Reactions: Reversibility of Chemical Reactions: EquilibriumEquilibrium
• Chemical reactions are reversible• Under certain conditions (concentration, temperature)
both reactants and products exist together in equilibrium state
H2 2H
2929
Reaction RatesReaction Rates
Net reaction rate = forward rate – reverse rate
• In equilibrium: Net reaction rate = 0• When reactants “just” brought together: Far
from equilibrium, focus only on forward rate• But, same arguments apply to the reverse rate
3030
The Differential Rate LawThe Differential Rate Law
• How does the rate of the reaction depend on concentration? E.g.
3A + 2B C + Drate = k [A]m[B]n
(Specific reaction)
rate constant
Order of reaction
with respect
to A
Order of reaction
with respect
to B
m+n: Overall order of
the reaction
3131
Rate Constants and Reaction OrdersRate Constants and Reaction Orders
• Each reaction is characterized by its own rate constant, depending on the nature of the reactants and the temperature
• In general, the order with respect to each reagent must be found experimentally (not necessarily equal to stoichiometric coefficient)
3232
Elementary Processes and Rate LawsElementary Processes and Rate Laws
• Reaction mechanism: The collection of elementary processes by which an overall reaction occurs
• The order of an elementary process is predictable
Unimolecular A* B K+ [A] First order
Bimolecular A + B C + D K+ [A] [B] Second order
Trimolecular A + B + C D + E K+ [A] [B] [C] Third order
3333
Elementary Processes and Rate LawsElementary Processes and Rate Laws
• Reaction mechanism: The collection of elementary processes by which an overall reaction occurs
• The order of an elementary process is predictable
Unimolecular A* B K+ [A] – K- [B] First order
Bimolecular A + B C + D K+ [A] [B] – K- [C] [D] Second order
TrimolecularA + B + C D + E
K+ [A] [B] [C] – K- [D] [E]
Third order
3434
dxS v
dt
Stoichiometry Matrix
Flux vectorConcentration vector
Constructing a pathway modelConstructing a pathway modelStep III - Dynamic mass balanceStep III - Dynamic mass balance
3535
A ‘simple’ ODE model of yeast glycolysis
3636
A model pathway system and its time-dependent behavior
Positive Feedback Loop
3737
A model pathway system and its time-dependent behavior
3838
A model pathway system and its time-dependent behavior