IDC 401:

THEORETICAL BIOLOGY

Modelling Genetic Regulatory Circuits

&
Simple Biochemical Pathways
Theoretical analysis of biochemical pathways and
gene regulation

• Introduction
• Types of feedback regulation in biochemical
pathways
• Different approaches for modelling biochemical
pathways
ü Gene circuits.
ü Network representation of biochemical
pathways
ü Modelling simple realistic pathways
 ANALYSIS OF BIOLOGICAL SYSTEMS

REDUCTIONIST
APPROACH

SYNTHETIC
APPROACH

BASIC UNIT OF LIFE

HOW DO CELLS WORK ?
 HOW DO CELLS WORK ?
F
L Transcription rate -
O ~ 1,000 nucleotides/min
W
Translation rate -
of ~ 900 amino acids/min
I
N Production of protein
F to the binding of dimer
O - about 3 min
R
M
A Information in
T nucleotide strings
I
O Dynamic Programming,
N Algorithms

Molecular Dynamics, Dynamical Systems Theory

Protein Structure Stat. Phys, Quantum Biochemical Network Theory,
& Folding Mech., Electrostatics, Pathways Differential Eqns,
Network Theory Boolean Algebra, Topology
Living systems are made up of cells – single or multi-cellular

Cellular functions are controlled by networks of biochemical reactions

Cellular behaviour is an
emergent property of networks
of inter-connected chemical
reactions of the molecular
species in the cell.

PHYSICS AND CHEMISTRY DRIVES ALL LIFE PROCESSES

https://www.genome.jp
/kegg/pathway.html

KEGG PATHWAY
Database
Wiring diagrams of
molecular interactions,
reactions and relations
 Amino acid
Metabolic pathways – scales of description
biosynthesis
pathways

Aromatic amino acid

biosynthesis pathway

Tryptophan
biosynthesis pathway
Tryptophan biosynthesis pathway

TrpG, TrpE

TrpD

TrpF

TrpC

TrpA, TrpB
Complex network of biochemical reactions in cells
co-ordinate and control cellular functions

two interacting sets

GENETIC METABOLIC
REACTIONS REACTIONS

Gene induction, Conversion of substrate

repression, molecules by enzymes,
replication, enzyme inhibition or
transcription activation

Slow TIME SCALE Fast

(minutes, hours) (seconds)
 Biochemical reactions are highly networked reactions

Primary mode of regulation to co-ordinate and control is through

Single, Multiple & Coupled Negative and Positive
Feedback Processes

a ck
d b desensitize the system to perturbations
fe e
ve It ensures stability and conservation of energy and
t i
ga are, therefore, naturally selected to be the most
Ne common form of regulation in pathways

a ck are potentially destabilizing

b
ed
fe Employed for excitable dynamics & amplification in
ive
s it switching & rapid response processes.
Po

A combination of negative and positive feedback processes

is useful for optimal performance requiring stability, sensitivity
and multiplicity of dynamics.
 Biochemical reactions are controlled and co-ordinated
mainly through feedback processes.
Most biosynthetic pathways have multiple levels of feedback control

Monovalent Divalent
Control Control

Nested Sequential
Control Control
isoenzymes

Concerted Cumulative
Control Control

Cascaded
Control
 Biosynthesis of Aromatic Amino Acids
b-Aspartyl kinase

Divalent, Nested and Sequential

control in bacteria

Gene Repression Concerted control of b - Asp.

kinase in Rhodopseudomonas
capsulatus

Enzyme inhibition

Dual nested feedback in E.coli tryptophan biosynthetic pathway

 EXPECTATIONS FROM THEORETICAL STUDIES

Identification of common features

in different pathways

Identification of differences in similar pathways

in different organisms
functional implications

Predict new behaviour

Design new pathways

Correct pathological states

Molecular Biology, Genetics, Biochemistry, Mathematics, Statistics,

Databases, Visualisation, Network Theory, Computational methods
 BIOCHEMICAL PATHWAYS ARE SEQUENTIAL REACTIONS
Information for short and long range regulation is transferred
primarily through feedback and feed-forward loops
Cellular behaviour is the emergent property of many complex biochemical
reactions networked through feedback/feed-forward processes with
overlapping and wide-ranging time scales

Biochemical details of each pathway may be different, but they possess

certain general features which can be described using the rules of chemical
kinetics.

The resultant dynamics underlie different functional behaviour

Stability – Homeostasis
Multistability – Ability to operate on alternative conditions
Threshold Sensitivity – Switching behaviour
Oscillatory – Rhythmic and cyclic processes
Chaotic – Bursting activity & irregular behaviour
Transient processes – Stochastic phenomena and spatial waves

Generality in dynamics across a large variety of biochemical

processes allow theoretical studies to be functionally meaningful & useful.
Cellular functions are controlled by networks of
biochemical reactions
 MODELLING BIOCHEMICAL PATHWAYS
Three complementary approaches
REVERSE ENGINEERING
Model existing pathways based on
information derived from –
• Genome sequences
• Protein sequences
• Biochemical & Genetic information
FORWARD ENGINEERING
All designs that are not physically
forbidden are realizable,
but not all realizable designs are
functionally effective
(in relation to context and constraints
of the system and environment).
LARGE NETWORKS
Construction & analysis of
functionally related
pathways from large scale
gene expression and
protein interaction data
using network theory
‘Rational Network
Design’
Artificial genetic and
enzymatic networks with
specific properties
constructed based on
mathematical models