LSM3241: Bioinformatics and Biocomputing Lecture 9: Biological Pathway Simulation Prof' Chen Yu Zong

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LSM3241 Bioinformatics and BiocomputingLecture
9 Biological Pathway Simulation Prof. Chen
Yu ZongTel 6874-6877Email yzchen_at_cz3.nus.edu.
sghttp//xin.cz3.nus.edu.sgRoom 07-24, level 7,
SOC1, NUS
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Biomolecular Interaction Enzyme Substrate
E S gt E P

• This is a generalization of how a biochemist
  might represent the function of enzymes.

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Biomolecular Interaction Enzyme Substrate
E S gt E P kinase-ATP complex
inactive-enzyme gt Kinase ADP active
enzyme
K
P
ATP
ADP

• Here is an example of the generalization
  represented by two different ways.

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Biomolecular Interaction Enzyme Substrate
Kinase-ATPcomplex
inactiveenzyme
Activeenzyme
ADP

• This is another representation.

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Spoke and Matrix Models of Protein-Protein
Interactions

• Vrp1 (bait), Las17, Rad51, Sla1, Tfp1, Ypt7

Possible Actual Topology
Matrix
Spoke
Theoretical max. no. of interactions, but many FPs
Simple model Intuitive, more accurate, but
canmisrepresent
BaderHogue Nature Biotech. 2002 Oct 20(10)991-7
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Synthetic Genetic Interactions in Yeast
Tong, Boone
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Metabolic Pathway ATP Production

• Glycolysis
• Phosphorylation
• Pyruvate
• Anaerobic respiration
• Lactate production
• 2 ATPs produced

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Cyclic Metabolic Pathway
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Methods of Metabolic Engineering
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Generic Signaling Pathway
Signal Receptor (sensor) Transduction
Cascade Targets Response
Metabolic Enzyme
Cytoskeletal Protein
Gene Regulator
Altered Metabolism
Altered Gene Expression
Altered Cell Shape or Motility
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Components of Signaling
What 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 LIGAND Ligand- A molecule that binds to
a specific site on another molecule, usually a
protein, ie receptor
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Components of Signaling
What are Receptors? Sensors, what the
signal/ligand binds to initiate ST
Hydrophillic Ligand
Cell-Surface Receptor
Cell surface Intracellular
Plasma membrane
Hydrophobic Ligand
Carrier Protein
Intracellular Receptor
Nucleus
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Generic Signal Transduction
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RTK Signal Transduction
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Signal Transduction Downstream effectors
Protein Signaling Modules (Domains)
SH2 and PTB bind to tyrosine phosphorylated
sites SH3 and WW bind to proline-rich
sequences PDZ domains bind to hydrophobic
residues at the C-termini of target proteins PH
domains bind to different phosphoinositides FYVE
domains specifically bind to Pdtlns(3)P
(phosphatidylinositol 3-phosphate)
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Mechanisms for Activation of Signaling Proteins
by RTKs
Activation by membrane translocation
Activation by a conformational change
Activation by tyrosine phosphorylation
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Mechanisms for Attenuation Termination of RTK
Activation
1) Ligand antagonists 2) Receptor antagonists 3)
Phosphorylation and dephosphorylation 4) Receptor
endocytosis 5) Receptor degradation by the
ubiquitin-proteosome pathway
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Activation of MAPK Pathways by Multiple Signals
Growth, differentiation, inflammation, apoptosis
-gt tumorigenesis
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Overview of MAPK Signaling Pathways
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The MAPK Pathway Activated by RTK
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P
RTK ST- PI3K pathway
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Apoptosis Pathways
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TGF Pathway
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Constructing a pathway modelthings 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.

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Constructing a pathway modelthings 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
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Constructing a pathway modelStep I - Definitions
We begin with a very simple imaginary metabolic
network represented as a directed graph
How do we define a biologically significant
system boundary?
Vertex protein/substrate concentration. Edge -
flux (conversion mediated by proteins of one
substrate into the other)
Internal flux edge
External flux edge
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Constructing a pathway modelStep II Interaction
Kinetics
E S gt E P kinase-ATP complex
inactive-enzyme gt Kinase ADP active
enzyme
K
P
ATP
ADP
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Reversibility of Chemical Reactions Equilibrium
H2 ? 2H

• Chemical reactions are reversible
• Under certain conditions (concentration,
  temperature) both reactants and products exist
  together in equilibrium state

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Reaction 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

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The Differential Rate Law

• How does the rate of the reaction depend on
  concentration? E.g.

mn Overall order of the reaction
3A 2B ? C D rate k AmBn
(Specific reaction) rate constant
Order of reaction with respect to A
Order of reaction with respect to B
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Rate 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)

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Elementary 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

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Elementary 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

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Constructing a pathway modelStep III - Dynamic
mass balance
Stoichiometry Matrix
Flux vector
Concentration vector
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A simple ODE model of yeast glycolysis
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A model pathway system and its time-dependent
behavior
Positive Feedback Loop
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A model pathway system and its time-dependent
behavior
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A model pathway system and its time-dependent
behavior