Chapter 8 Applications

In physics
In biology
In chemistry
In engineering
In political sciences
In social sciences
In business

In chemistry chemical reaction
Biochemical reactions:
Take place in all living organisms
Most of them involve proteins called as enzymes
Enzymes react selectively on compounds: substrates
Biological & biochemical processes are complicated
Develop a simplifying model to understand the phenomena
Give qualitative understanding
First step to develop more realistic & complicated model
Reaction kinetics
Basic enzyme reaction: Michaelis & Menten (1913)
A substrate S reacting with an enzyme E to form a complex SE
The complex SE is converted into a product P and the enzyme





The laws of mass action: the rate of a reaction is
proportional to the product of the concentrations of the reactants
1 2
1
1 1 2
,
: reaction is reversible & : reaction can go only one way
, & : constant parameters associated with the rates of reaction
k k
k
S E SE SE P E
k k k

+ +

Reaction equations
Concentrations of the reactants:

Nonlinear reaction equations


Explain: The first equation for s is simply the statement that the rate of
change of the concentration [S] is made up of a loss rate proportional to [S] [E]
and a gain rate proportional to [SE].
[ ], [ ], [ ], [ ] s S e E c SE p P = = = =
1 1 1 1 2
1 1 2 2
, ( ) ,
( ) , ;
ds de
k e s k c k e s k k c
dt dt
dc dp
k e s k k c k c
dt dt

= + = + +
= + =
Model reduction
Initial conditions:

The last equation is uncoupled

Conservation of enzyme: catalyst

Reduced system


0 0
(0) , (0) , (0) 0, (0) 0 s s e e c p = = = =
0 0
0 ( ) ( ) 0
de dc
e t c t e e
dt dt
+ = + = + =
2 2 2
0 0 0
( ) (0) ( ') ' 0 ( ') ' ( ') '
t t t
p t p k c t dt k c t dt k c t dt = + = + =
} } }
1 0 1 1 1 0 1 1 2
( ) , ( )
ds dc
k e s k s k c k e s k s k k c
dt dt

= + + = + +
Pseudo-steady state
Pseudo-steady state solution: The reaction of complex to product
is much faster than that of substrate to complex, i.e. enzyme is almost at
equilibrium



The equation
1 1 2
0
1 0
1 1 2
1 2 1
0 ( ) 0

( 0 ) ( ) 0
de
k e s k k c
dt
e e c
k e s
k e c s k k c c
k k k s

~ + + ~
=
+ + ~ ~
+ +
1 2 0
1 1 2
1 2 1
k k e s ds
k s e k c k c
dt k k k s

= + ~ =
+ +
Pseudo-steady state solution
Define Michaelis constant
Pseudo-steady state solution

Determine rate of reaction v
Take a sequence of different initial values of
Measure the corresponding variation of s with t,
Rate of reaction
Obtain for each experiment a measurement of the initial rate
1 2
1
m
k k
K
k

+
=
0 2 0
( )
2 0
0
( ) , 0
m m
K s K k e t s t
m
ds k e s
e s t e s e t
dt s K

= = >
+
0
s
0
( ; ) s s t s =
2 0
m
k e s dp ds
v
dt dt s K
= ~ =
+
0 2 0 2 0 0
1 1 1
m
K
v k e k e s
= +
Lineweaver-Burk plot
Michaelis-Menten rate
Qualitative analysis
Nondimensionalization:

Dimensionless equation


Qualitative understanding
Steady state: u=v=0
v increases from v=0 until attains its maximum at v=u/(u+K) then decreases to v=0
u decreases monotonically from u=1 to u=0
0 2 1 2
1 0
0 0 1 0 1 0 0
( ) ( )
, ( ) , ( ) , , ,
e k k k s t c t
k e t u v K
s e k s k s s
t t t c

+
= = = = = =
( ) , ( )
(0) 1, (0) 0
du dv
u u K v u u K v
d d
u v
c
t t
= + + = +
= =
Qualitative analysis
Michaelis-Menhten theory
Pseudo-steady state hypothesis: The remarkable catalytic
effectiveness of enzymes is reflected in the small concentrations needed in
their reactions as compared with the concentrations of the substrates.

Approximate (asymptotic) solution:
Assume

Substitute and equate powers of
The O(1) equations:

2 7
0 0 0 0
/ 1: typically :10 10 e s e s c c

=
0 1 c <
0 0
( ; ) ( ) , ( ; ) ( )
n n
n n
n n
u u v v t c c t t c c t

= =
= =

c
0
0 0 0 0 0 0
0 0
( ) , 0 ( )
(0) 1, (0) 0
du
u u K v u u K v
d
u v

t
= + + = +
= =
Michaelis-Menten theory
Solution: (nonsingular or outer solution, valid for )





Difficulty: The second equation is algebraic & does not satisfy the initial condition


1
0(0) 1 (0) 0
1
u v
K
= = =
+
0 0 0 0
0 0 0
0 0 0
0 0
0
0
0 0 0
0
( )
( ) ln ( )
u (0)=1 A=1
( )
u ( )+K ln ( ) , ( ) , 0.
( )
u du u u
v u u K
u K d u K u K
u K u A
u
u A v
u K

t
t t t
t
t t t t t
t
= = + + =
+ + +
+ =

= = >
+
0
(1) o t t > =
Michaelis-Menten theory
The solution is not a uniformly valid approximation for all
The original problem is a singular perturbation problem since the
second equation is multiplied by a small parameter
The assumption is not valid near
Initial layer exists
Introduce the transformations

New equations
0 t >
0 1 c <
( )
dv
O
d
c c
t
= 0 t =
0 t =
, ( ; ) ( ; ), ( ; ) ( ; ) u U v V
t
o t c o c t c o c
c
= = =
( ) , ( ) ,
(0) 1, (0) 0
dU dV
U U K V U U K V
d d
U V
c c
o o
= + + = +
= =
Michaelis-Menten theory
Assume

O(1) equations


The solutions (singular or inner solution, valid for )

0 0
( ; ) ( ) , ( ; ) ( )
n n
n n
n n
U U V V o c c o o c c o

= =
= =

0 0
0 0 0
0 0
0, ( )
1, 0
dU dV
U U K V
d d
U V
o o
= = +
= =
1
0 0
( ) 1, ( ) (1 ) (1 exp[ (1 ) ]) U V K K o o o

= = + + +
0 1 t s
Michaelis-Menten theory
Matching:
The limit of the outer solution when
The limit of the inner solution when

Initial (or boundary) layer:
let 0, for a fixed 0 1 c t o <
0 c
o
0 0 0 0
0
1
lim [ ( ), ( )] [1, ] lim [ ( ), ( )]
1
U V u v
K
o t
o o t t

= =
+
1 1
0
0
| 1
dV dV
d d
t
c c
t o

=
=
Michaelis-Menten theory
Singular perturbation, a systemic way
Outer solution in the form of a regular series expansion




Inner solution expansion
0
0 0 0 0 0 0
0 1
1 0 0 1 1 0 0 1
(1) : ( ) , 0 ( )
O( ): ( 1) ( ) , (1 ) ( )
du
O u u K v u u K v
d
dv du
u v u K v u v u K v
d d

t
c
t t
= + + = +
= + + = +
0 0
0 0 0
1 1
0 0 0 0 1 0 1
(1) : 0, ( )
( ) : ( ) , (1 ) ( )

dU dV
O U U K V
d d
dU dV
O U V K V V U V K V
d d
o o
c
o o
= = +
= + + = +
Michaelis-Menten theory
Initial conditions:



Thus the singular solutions are determined completely

Outer solutions



Matching of the inner and outer solutions

0 0 o t = =
0 1
0
0
0
1 (0; ) (0) (0) 1, (0) 0
0 (0; ) (0) (0) 0
n
n n
n
n
n n
n
U U U U
V V V
c c
c c

>
=

>
=
= = = =
= = =

1
0 0
( ) 1, ( ) (1 ) (1 exp[ (1 ) ]) U V K K o o o

= = + + +
0 0 0 0
0
lim [ ( ), ( )] lim [ ( ), ( )] U V u v
o t
o o t t

=
0
0 0 0
0
( )
u ( )+K ln ( ) , ( ) , 0
( )
with A the constant of integration
u
u A v
u K
t
t t t t t
t
= = >
+
Michaelis-Menten theory




Uniformly expansion



0 0 0
0
0
0 0 0
0
0
0 0 0
lim ( ) 1 lim ( ) (0)
(0) 1
lim ( ) lim ( ) (0)
1 (0)
(0) 1 (0) ln (0) 1
U u u
u
V v v
K u K
u u K u A A
o t
o t
o t
o t


= = =
= = = =
+ +
= + = =
0 0 0
1
0 0
0
0 0
0
( ; ) ( ) ( ); ( ) ln ( ) 1
( ) ( ); ( ) (1 ) 1 exp( (1 ) , 0 1;
( ; )
( )
( ) ( ); ( ) , 0
( )
u u O u K u
V O V K K
v
u
v O v
u K
t c t c t t t
t
o c o t
c
t c
t
t c t c t
t

= + + =

| |
+ = + + s
|
\ .
=

+ = <

Michaelis-Menten theory
Michaelis-Menten theory
Uniformly matched asymptotic expansion: inner+outer-middle




Explain
Rapid change in substrate-enzyme takes place in dimensionless time
Very short, in many experimental cases, singular solutions is not observed
The reaction for the complex is essentially in a steady state
The v-reaction is so fast it is more or less in equilibrium at all times
This is Michaelis and Mentens pseudo-steady state hypothesis
0 0 0 0
0 0
1
0
0
( ; ) ( ) 1 1 ( ) ( ) ( ); ( ) ln ( ) 1
1
( ; ) ( ) ( ) ( )
1
( ) 1
(1 ) 1 exp( (1 ) ( ); 0
( ) 1
u u O u O u K u
v V v O
K
u
K K O
u K K
t c t c t c t t t
t c o t c
t t
c t
c t

= + + = + + =
= + +
+
| |
= + + + + >
|
+ +
\ .
( ) O t c =
Other chemical reactions
Cooperative phenomena

Enzyme has more than one binding site for substrate molecules
An enzyme + a substrate is called as cooperative: if a single enzyme molecule,
after binding a substrate molecule at one site can then bind another substrate
molecule at another site.
Example: enzyme molecule E binds a substrate molecule S to form a single
bound substrate-enzyme complex C1. C1 can break to form a product P and
enzyme E & combine with another substrate molecule S to form a dual bound
substrate-enzyme complex C2. C2 breaks down to form the product P and single
bound complex C1.
Autocatalysis, Activation & Inhibition: systems with feedback controls
3 1 2 4
1 3
1 1 2 1
,
k k k k
k k
S E C E P S C C P C

+ + + +
1 2
1
2 ,
k k
k
A X X B X C

+ +
Other models
Biological oscillators & switches: Feedback control






Reaction diffusion, Chemotaxis