Applied Mathematics and Computation 218 (2012) 75627572

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Applied Mathematics and Computation

journal homepage: www.elsevier.com/locate/amc

Bi-objective optimization of biochemical systems by linear programming

Gongxian Xu
Department of Mathematics, Bohai University, Jinzhou 121000, China

a r t i c l e

i n f o

Keywords:
Bi-objective optimization
Linear programming
S-system
Minimax problem
Biochemical systems

a b s t r a c t
This paper proposes an iterative strategy to address the bi-objective optimization of biochemical systems. The biochemical system is rstly represented by the S-system formalism
that steady-states can be explicitly represented as systems of linear algebraic equations.
Then a minimax method is used iteratively to maximize the performance of a biochemical
system while minimizing its cost. To illustrate the effectiveness of our theoretical results,
the fermentation pathway in Saccharomyces cerevisiae is analyzed. Compared with existing
optimization results in the literature, we also show that our results are better than existing
ones with this illustrative biochemical system.
2012 Elsevier Inc. All rights reserved.

1. Introduction
In the last decades, much research has been directed toward the development of model-based optimization strategies for
biochemical systems [122]. One successful approach to the optimization of biological systems is the Indirect Optimization
Method (IOM) [6,7,1520,22], which is based on a modeling framework called Biochemical Systems Theory (BST) [2329].
The hallmark of this theory is the approximation of the original nonlinear differential equation models describing the biological process as an S-system or a GMA system, among which the most relevant formulation is the S-system. The advantage
of this representation is that the steady-state equations are linear when the variables of the models are expressed in logarithmic coordinates. This enables the use of linear programming techniques.
In [22] a modied iterative IOM method was proposed and applied to the fermentation pathway in Saccharomyces cerevisiae. The research results in [22] have demonstrated that the modied iterative IOM approach has a better behavior than its
previous version in dealing with the model uncertainty of S-system. This approach only maximizes the production rate of
ethanol, but not minimize the metabolic cost. An abnormally high protein or intermediate concentration would cause the
biochemical system non-viable, with the burden on the cellular metabolism being too high for the cell to survive or the cellular osmolarity constraint violated [17,18]. In this paper, we present an iterative algorithm to simultaneously optimize
these two conicting objectives. The bi-objective optimization problem of a biochemical system is rstly proposed and is
then transformed into a bi-objective linear problem within the S-system modeling framework. Finally, a minimax method
is used to transform the bi-objective linear problem into a single-objective linear problem that can be easily solved with
the available optimization algorithms. The fermentation pathway in S. cerevisiae is performed to show the proposed framework of iterative optimization.
In the following, we rst describe the bi-objective problem of optimizing a biochemical system. This is followed by the
development of a linear optimization method to solve the bi-objective problem. Then the fermentation pathway in S. cerevisiae is chosen as a case study and is presented in terms of simulation experiments. Finally, brief conclusions are given in
Section 5.

E-mail address: dutxugx@yahoo.com.cn

0096-3003/$ - see front matter 2012 Elsevier Inc. All rights reserved.
doi:10.1016/j.amc.2012.01.023

G. Xu / Applied Mathematics and Computation 218 (2012) 75627572

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2. Optimization problem statement

Consider the following bi-objective problem of optimizing a biochemical system:

max

J 1 X; Y

min

J 2 X; Y

subject to satisfying:

F i X; Y 0;

i 1; 2; . . . ; n;

X Li 6 X i 6 X Ui ;

Y Lk 6 Y k 6 Y Uk ;

k 1; 2; . . . ; m;

Gl X; Y 6 0;

l 1; 2; . . . ; p;
T

where X = (X1, X2, . . . , Xn) 2 R , Y = (Y1, Y2, . . . , Ym) 2 R ; the objective function J1 is usually a ux or a particular metabolite
concentration; J2 is the metabolite cost, which is the total amount of metabolite concentrations or total amount of enzyme
activities; constraint (3) is the steady-state condition (i.e., dXi/dt = 0); constraints (4) and (5) keep the metabolite concentrations Xi and the enzyme activities Yk to stay within certain limits; and (6) forces a ux or the ratio of some two uxes to
remain below a certain limit. Due to the product nature of the uxes, constraint (6) becomes linear in logarithmic space.
3. Linear optimization methods
3.1. The S-system formalism
The S-system formalism is based on BST which proposes the use of power law functions to describe the nonlinear nature
of biochemical processes [26]. Under this representation, the elementary uxes consisting of input uxes and output ones
are grouped into aggregate uxes that pass into and out of metabolic pools. These aggregate uxes have forms given by

accumulation ux V
i and consumption V i . Then the original model:

dX i
F i X; Y;
dt

i 1; 2; . . . ; n

can be expressed as:

dX i
V i  V i ;
dt

i 1; 2; . . . ; n:

If each of these rate laws is represented in the power law formalism, then yields the S-system model of Eq. (7):
n
m
n
m
Y
Y
Y
Y
dX i
g0
g
h
h0
X j ij
Y kik  bi
X j ij
Y kik ;
ai
dt
j1
j1
k1
k1

i 1; 2; . . . ; n;

where the model parameters gij, g 0ik , hij and hik are the kinetic orders, and ai and bi are the rate constants. The kinetic orders
are dened as:


g ij

@V i X j
@X j V i

g 0ik

@V i Y k
@Y k V i


;
0

hij

 

@V i X j
;

@X j V i 0

hik

 

@V i Y k
:

@Y k V i 0

And the rate constants are dened as:

ai V i 0

n
Y

g ij

X j 0

j1

m
Y

g 0ik

Y k 0

and bi V i 0

n
Y
j1

k1

hij

X j 0

m
Y
h0
Y k 0 ik ;
k1

where the subscript 0 indicates that the results are evaluated at the steady-state of metabolite concentrations. Based on Eq.
(9) the objective functions J1(X, Y) and J2(X, Y) can also be written as the following S-system forms, respectively:

J 01 X; Y c1

n
Y

X i1i

i1

J 02 X; Y c2

n
Y
i1

m
Y

f0

Y k1k ;

10

k1

X i2i

m
Y

f0

Y k2k ;

k1

0
0
where f1i, f1k
, f2i and f2k
terms stand for the kinetic orders, and c1 and c2 represent the corresponding rate constants.

11

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G. Xu / Applied Mathematics and Computation 218 (2012) 75627572

Although S-system models are nonlinear, the steady-state equations are linear when the variables are expressed in logarithmic coordinates [24]. This allows us to use the linear programming techniques [12,15,20].
At the non-trivial steady-state the S-system (9) reduces to the following nonlinear equations:

 
n
m
X
X
b
0
g ij  hij lnX j
g 0ik  hik lnY k ln i ;
j1

ai

k1

i 1; 2; . . . ; n:

12

Let xj = ln(Xj), j = 1, 2, . . . , n, yk = ln (Yk), k = 1, 2, . . . , m and bi = ln(bi/ai), i = 1, 2, . . . , n, then Eq. (12) can be recast in a form
of linear algebraic equations:

Ad x Aid y b;

13
g 0ik

0
hik nm ,

where the matrices Ad = (gij  hij)nn, Aid


the vectors x = (x1, x2, . . . , xn) , y = (y1, y2, . . . , ym) and b = (b1, b2, . . . ,
bn)T. The inverse of the matrix Ad exists if the biochemical system has a non-zero steady-state point [26]. Thus, x can be
solved by Eq. (13):
1
xy; b A1
d Aid y Ad b:

14

Due to the fact that the logarithmic transformation does not change the locations of maximum/minimum of a function,
the nonlinear optimization problem in Section 2 can be transformed to the following linear programming formulations:

max
min

J 1 x; y
J 2 x; y

subject to satisfying :
Ad x Aid y b;

15

lnX Li 6 xi 6 lnX Ui ;

i 1; 2; . . . ; n;

lnY Lk 6 yk 6 lnY Uk ;

Gx; y 6 0;

k 1; 2; . . . ; m;

 y 2 Rl is the linear representations of constraint (6) in logarithmic space, and the new objecwhere the vector function Gx;


tive functions J 1 x; y and J 2 x; y can be expressed respectively as:

J 1 x; y lnJ X; Y lnJ 0 X; Y lnc

1
1
1

n
X

f1i lnX i

i1

m
X

0
f1k
lnY k lnc1

n
X

f1i xi

i1

k1

m
X

0
f1k
yk

k1

lnc1 f1T x f10T y;

J 2 x; y lnJ X; Y lnJ 0 X; Y lnc
2
2
2

16
n
X
i1

lnc2 f2T x f20T y;

f2i lnX i

m
X
k1

0
f2k
lnY k lnc2

n
X
i1

f2i xi

m
X

0
f2k
yk

k1

17

0
0
0
0
0
0
where f1 = (f11, f12, . . . , f1n)T, f10 f11
; f12
; . . . ; f1m
T , f2 = (f21, f22, . . . , f2n)T, f20 f21
; f22
; . . . ; f2m
T .
Note that, to ensure that the optimum solution is within the physiologically acceptable range of values, the following relations are imposed [17,29]:

X Li 0:8X i 0

and X Ui 1:2X i 0 ;

18

where (Xi)0 is the steady-state of Xi.

3.2. The minimax formalism
Many techniques have been suggested for dealing with a bi-objective optimization problem in the last decades. In this
work, we propose the following minimax formalism of problem (15):

min

maxfJ1 x; y; J 2 x; yg

subject to satisfying :
Ad x Aid y b;
lnX Li 6 xi 6 lnX Ui ;

i 1; 2; . . . ; n;

lnY Lk 6 yk 6 lnY Uk ;
 y 6 0:
Gx;

k 1; 2; . . . ; m;

19

G. Xu / Applied Mathematics and Computation 218 (2012) 75627572

7565

To avoid scaling issues, the objective functions are scaled between 0 and 1 as shown in Eq. (20)

min

(
)
J 1 x; y  J min
J max  J 2 x; y
1
max ^J 1 x; y max min
; ^J 2 x; y 2max min
J1  J1
J2  J2

subject to satisfying :
Ad x Aid y b;

20

lnX Li 6 xi 6 lnX Ui ;

i 1; 2; . . . ; n;

lnY Lk 6 yk 6 lnY Uk ;
 y 6 0;
Gx;

k 1; 2; . . . ; m;

where J max
, J max
, J min
and J min
are the approximated maximum and minimum values of the objective functions J 1 x; y and
1
2
1
2
J 2 x; y respectively. They can be found easily by

J max lnc
1
1

f1i lnX Ui

i2I11

J max lnc
2
2

f2i lnX Ui

f1i lnX Li

f2i lnX Li

f1i lnX Ui

i2I12

f2i lnX Li

i2I21

0
f1k
lnY Uk

k2K 11

i2I22

i2I11

J min lnc
2
2

f1i lnX Li

i2I12

i2I21

J min lnc
1
1

0
f2k
lnY Uk

i2I22

X
k2K 21

21

0
f2k
lnY Lk ;

22

0
f1k
lnY Uk ;

23

0
f2k
lnY Uk ;

24

X
k2K 22

0
f1k
lnY Lk

k2K 11

f2i lnX Ui

0
f1k
lnY Lk ;

k2K 12

k2K 21

X
k2K 12

0
f2k
lnY Lk

X
k2K 22

0
where I11 fiji 2 I; f1i P 0g, I12 = {i|i 2 I, f1i < 0}, I21 fiji 2 I; f2i P 0g, I22 = {i|i 2 I, f2i < 0}, K 11 fkjk 2 K; f1k
P 0g,
0
0
0
K 12 fkjk 2 K; f1k
< 0g, K 21 fkjk 2 K; f2k
P 0g, K 22 fkjk 2 K; f2k
< 0g with I = {1, 2, . . ., n} and K = {1, 2, . . ., m}.

3.3. Reformulation of the minimax problem

Problem (20) is a linear minimax problem. To handling it efciently, we will try to reformulate the concerned problem as
a classical minimization problem by introducing an additional variable. Then some well developed solution methods for linear programming problems, such as the interior point methods, can be applied to solve it.
Dening a variable t, which is equal to the maximum of ^J 1 x; y and ^J 2 x; y, the minimax problem (20) can be stated as the
following linear optimization problem:

min

subject to satisfying :
^J 1 x; y 6 t;
^J 2 x; y 6 t;
J 1 x; y P J 10 ;

25

J 2 x; y 6 J 20 ;
Ad x Aid y b;
lnX Li 6 xi 6 lnX Ui ;

i 1; 2; . . . ; n;

lnY Lk

k 1; 2; . . . ; m;

6 yk 6
 y 6 0;
Gx;

lnY Uk ;

where J 10 and J 20 denote the values of J 1 x; y and J 2 x; y respectively at the steady-state of metabolite concentrations. The
introduction of constraint J 1 x; y P J 10 and J 2 x; y 6 J 20 into problem (25) guarantees that the optimized results of both
J 1 x; y and J 2 x; y are not inferior to those obtained at the basal steady-state.
Since the S-system formalism is a local description of the original system at a basal steady-state based on rst order
Taylors approximations, we may not obtain the correct optimum steady-state of bi-objective nonlinear problem (1)(6)
by solving linear problem (25). To overcome this difculty of running into a range of local solution and enhance the effectiveness of the approximate approach, it is necessary to make an improvement in the scheme of problem (25). In this study,
we propose the following modied form of problem (25) grounded on the similar thought of the modied iterative IOM
approach [22]:

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G. Xu / Applied Mathematics and Computation 218 (2012) 75627572

min ft  kT w; byg
t;y

subject to satisfying :
Hxy; b; y; t 6 0;
lnX Li
lnY Lk

6
6

xi 6 lnX Ui ;
yk 6 lnY Uk ;

26
i 1; 2; . . . ; n;
k 1; 2; . . . ; m;

where
1
xy; b A1
d Aid y Ad b; Hxy; b; y; t
T

Gxy;
b; y ^J 1 xy; b; y  t ^J 2 xy; b; y  t J 10  J 1 xy; b; y J 2 xy; b; y  J 20 

and kw; b is the multiplier that can be expressed as:

#

T "
@ ^xw
@ T Hxw; b; w; t
kw; b A1
A

g

g

g
id
1
2
3 ;
d
@w
@x

27

where @ ^
xw=@w can be obtained from wk = (yk)0 (k = 1, 2, . . ., m) and the following relation:



@ ^xi yk
@X i Y k 

;
@yk
@Y k X i Xi X i 0 ;Y k Y k 0

i 1; 2; . . . ; n; k 1; 2; . . . ; m

where ((Xi)0, (Yk)0) (i = 1, 2, . . ., n) is a non-zero steady-state point of the system (7).

In fact, we have an implicit function F(X, Y) (F(X, Y) 2 Rn) along with a valid solution for F(X, Y) = 0, then the implicit function theorem [30,31] can be used to compute @X/@Y. Because F(X, Y) is continuously differentiable around its steady-state
solution, we can write


1
@X
@FX; Y
@FX; Y

:
@Y
@X
@Y

28

Then @ ^
xy=@y can be computed by the following matrix operation of Hadamard product [32]:

@ ^xy @X

M
@y
@Y

29

with



 
@ ^xy
@X

Mik
@y ik
@Y ik
and

2Y

X1

6
6 Y1
6 X2
M6
6 .
6 ..
4

Y1
Xn

Y2
X1

...

Ym
X1

Y2
X2

...

Ym
X2

..
.
Y2
Xn

..

...

7
7
7
7:
.. 7
. 7
5

Ym
Xn

Comparing with problem (25), an extra linear term that contains a comparison of metabolite concentration derivatives
with respect to the enzyme activities between the S-system and the original model is introduced in (26). This variant will
also keep the modied optimization problem solved with available linear programming techniques. Now we summarize
the following iterative algorithm for bi-objective optimization of biochemical systems:
Step 0. Choose a steady-state point (X0, Y0), initial multiplier g01 , g02 and g03 , g01 ,g02 ; g03 P 0, relaxation coefcients h1, h2, h3
and h4, 0 < h1 6 1, h2, h3, h4 > 0, some solution accuracy e, e > 0. Set r = 0.
Step 1. Apply Yr to the system (3) and nd the concentrations Xr. Transfer system (7) and objective functions J1(X, Y) and
J2(X, Y) to the S-system forms.
Step 2. Calculate @ ^
xy=@y by Eq. (29).
r
^r y
^r yr ; br ; gr1 ; gr2 ; gr3 )
Step 3. For w = yr, b = br and kw; b kyr ; b , solve the modied optimization problem (26). Let y
r
r
r
r
r
r
^ expy
^ 1; l
^ 2; g
^r1 ; expy
^r2 ; . . . ;
^1 ; g
^ 2 and g
^ 3 . Denote Y
be the solution, with the corresponding multipliers l
T
r
^
expym .
^ r  Y r jj 6 e; jjg
^ r1  gr1 jj 6 e; jjg
^ r2  gr2 jj 6 e and jjg
^ r3  gr3 jj 6 e; then transfer the results to the original model and
Step 4. If jjY
stop.
Step 5. Update enzyme activities and multiplies:

G. Xu / Applied Mathematics and Computation 218 (2012) 75627572

7567

Y r1 Y r h1 Y^ r  Y r ;

30

r
r
^r
gr1
i 1; 2; . . . ; n;
1i max0; g1i h2 g1i  g1i ;

31

r
r
^r
gr1
i 1; 2; . . . ; n;
2i max0; g2i h3 g2i  g2i ;

32

r
r
^r
gr1
l 1; 2; . . . ; p:
3l max0; g3l h4 g3l  g3l ;

33

Set r = r + 1 and continue from Step 1.

Remark 1. After substituting the optimized enzyme activities of Step 3 into Eq. (13), we obtain the steady-state of the Ssystem model (9). This steady-state is called the S-system solution [6,17]. After substituting the optimized enzyme activities
of Step 3 into Eq. (3), we obtain the steady-state of the original model (7). This steady-state is called the IOM solution [6].
4. Case study
To illustrate the calculation algorithm, we will apply the proposed optimization method to the production of ethanol by S.
cerevisiae. The experimental model of this pathway in a suspended cell culture at pH 4.5 was originally proposed in [33,34]
and transformed into an S-system and studied for ethanol production maximization by [35,16]. The simplied pathway is
depicted graphically in Fig. 1 and its model is described as follows (see [33,34]):

dX 1
V in  V HK ;
dt

34

dX 2
V HK  V PFK  V Pol ;
dt

35

dX 3
V PFK  V GAPD  0:5V Gol ;
dt

36

dX 4
2V GAPD  V PK ;
dt

37

dX 5
2V GAPD V PK  V HK  V Pol  V PFK  V ATPase ;
dt

38

where Xi represent the following intermediate metabolite concentrations: X1 is the intracellular glucose concentration, X2
represents glucose 6-phosphate, X3 codes for fructose 1, 6-diphosphate, X4 is phosphoenolpyruvate, and X5 represents
ATP. The indexed quantities V represent the following uxes: Vin denotes the sugar transport into the cells, VHK summarizes
all hexokinases, VPFK is the phosphofructokinase reaction, VGADP represents glyceraldehyde 3-phosphate dehydrogenase, VPK

Fig. 1. Anaerobic fermentation pathway in Saccharomyces cerevisiae.

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G. Xu / Applied Mathematics and Computation 218 (2012) 75627572

represents pyruvate kinase, VPol describes glycogen synthetase, VGol, the glycerol 3-phosphate dehydrogenase is proportional
to VPK, and VATPase summarizes collectively the use of ATP. Their corresponding kinetics are given in the appendix.
The bi-objective optimization problem is dened to maximize the rate of ethanol production (which is given directly by
the ux through the pyruvate kinase, VPK) and simultaneously minimize the ve metabolite concentrations, subject to a set
of constrains to assure steady-state and cell viability. The resulting bi-objective optimization problem is as follows:

max

J 1 V PK

min

J2

5
X

Xi

i1

subject to satisfying:

V in  V HK 0;
V HK  V PFK  V Pol 0;
V PFK  V GAPD  0:5V Gol 0;
2V GAPD  V PK 0;

39

2V GAPD V PK  V HK  V Pol  V PFK  V ATPase 0;

0:8X i0 6 X i 6 1:2X i0 ;
Y k0 6 Y k 6 50Y k0 ;

i 1; 2; 3; 4; 5;

k 1; 2; 3; 4; 5; 8;

V PK 6 2V in ;
Y 6 ; Y 7 ; Y 9 14:31; 203; 0:042:
This is a bi-objective nonlinear optimization problem with complex constrains.
At the initial steady-state (see Table 1), the dynamical model of the pathway is transformed into the following S-system
formalism [22]:

dX 1
Y 1  2:8661X 0:7464
X 0:0244
Y 2;
0:8122X 0:2344
2
1
5
dt

40

dX 2
X 0:0244
Y 2  0:5239X 0:7388
X 0:3937
Y 0:9991
Y 0:0009
;
2:8661X 0:7464
1
5
2
5
3
6
dt

41

dX 3
X 0:3941
Y 3  0:0148X 0:5843
X 0:0297
X 0:119
Y 0:9443
Y 0:0557
Y 0:5749
;
0:5231X 0:7318
2
5
3
4
5
4
7
9
dt

42

dX 4
X 0:1308
Y 4 Y 0:6088
 0:0946X 0:0499
X 0:533
X 0:0822
Y5;
0:0221X 0:6159
3
5
9
3
4
5
dt

43

Table 1
Optimal solutions obtained by using the proposed optimization approach.a

Variables

Initial steady-state

X1
X2
X3
X4
X5
Y1
Y2
Y3
Y4
Y5
Y8
J1
J2

0.0345
1.0111
9.1437
0.0095
1.1278
19.7
68.5
31.7
49.9
3440
25.1
30.1124
11.3266

Optimized solutions (30 iterations)

S-system

IOM

0.0436
1.9109
12.3613
0.0228
1.7038
960.6243
3425
1585
2495
172000
1112.0548
1900.9228
16.0424

0.0436
1.9109
12.3613
0.0228
1.7038
960.6243
3425
1585
2495
172000
1112.0548
1900.9228
16.0424

The denition of the S-system and IOM solutions is given in Remark 1 of Section 3.3.

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G. Xu / Applied Mathematics and Computation 218 (2012) 75627572

dX 5
0:5 0:3044
X 0:2665
X 0:0243
Y 0:5
 3:2105X 0:1978
X 0:1958
X 0:3722
Y 0:265
Y 0:2648
Y 0:0002
Y 0:47
:
0:0914X 0:3329
3
4
5
4 Y5 Y9
1
2
5
2
3
6
8
dt

44

The S-system models of the objective functions J1 and J2 are written respectively as:

J 01 X; Y 0:0946X 0:0499
X 0:533
X 0:0822
Y5;
3
4
5

45

X 0:0893
X 0:8073
X 0:0008
X 0:0996
:
J 02 X 1:8999X 0:003
1
2
3
4
5

46

After substituting the power-law terms for Vin and VPK from Eqs. (34) and (37), the nonlinear constraint V PK 6 2V in
becomes

0:0946X 0:0499
X 0:533
X 0:0822
Y 5 6 1:6244X 0:2344
Y 1:
3
4
5
2

47

The simulation experiments of optimization problem (39) using the proposed approach were performed. The following
algorithm parameters were assumed in the method: h1 = 0.9, h2 = h3 = h4 = 0.8, g01i g02i 0:1; g03 0:1. Fig. 2 presents the
trajectories generated by the algorithm starting from the initial steady-state given in Table 1. It can be seen that the optimization strategy yields the consistent S-system and IOM solutions with a rate of ethanol production increased more than
63.13 times its initial steady-state and a total concentrations of J2 = 16.0424 (see Table 1). The optimized results within 30
iterations are given in Table 1.
Table 2 shows a comparative study between the bi-objective and mono-objective optimization results, where s = J2/J1 denotes the transition time [36] and w J 21 =J 2 is a criterion for evolutionary effectiveness [37]. A metabolic system with short
transition time reaches the steady-state rapidly. It also transforms substrate into nal product faster than other systems with
longer transition time. It is rather obvious that shortening of the transition time is a desirable goal in biotechnology [17].
While the best-adapted metabolic systems should exhibit high values of w [17]. Examination of Table 2 shows that a significant improvement in both s and w can be attained through the use of the proposed approach. The transition time s changes
from 0.3761 in the original setup down to 0.0084, that is, just a 2.23% of its initial value. Moreover, the metabolic performance w changes from 80.0555 to 225247.3128, more than 2813.6394 times its original value. Table 2 also provides us with
a comparison of these results with those obtained by other mono-objective approaches. One type of approach used to deal
with this kind of complex nonlinear optimization problem addressed is the use of the modied iterative IOM method presented in [22]. Using the modied iterative IOM method, these authors found out the optimization results shown in Table 2.
As can be seen for the J1 value, the bi-objective optimization yields a slightly lower rate of ethanol production than the
mono-objective approach in [22]. However, for the three responses considered, J2, s and w, the results obtained with the
bi-objective optimization are better than the mono-objective approach in [22], with improvements in about 43.25%,

2500

(a)

2000

J1

1500
1000
500
0

S-system solution
IOM solution
0

17

10

15
Iterations

20

25

30

(b)

16

J2

15
14
13
12
11

S-system solution
IOM solution
0

10

15
Iterations

20

25

30

Fig. 2. Variation of optimization indexes for case study during the proposed optimization approach: (a) J1; (b) J2.

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G. Xu / Applied Mathematics and Computation 218 (2012) 75627572

Table 2
Comparison of performances.a
Indexes

Initial values

Bi-objective optimization

Mono-objective optimization

J1(max)
J2(min)
s = J2/J1(min)

30.1124
11.3266
0.3761
80.0555

1900.9228
16.0424
0.0084
225247.3128

1952.1568
28.2663
0.0145
134821.8965

w J21 =J2 (max)

a

The mono-objective calculation results correspond to the optimization of the same system by using the modied iterative IOM method [22].

42.07% and 67.07% respectively. These conclusions clearly show the tractability and effectiveness of the presented optimization algorithm in handling bi-objective optimization of biochemical systems with nonlinear constraints.
5. Conclusions
In this work, a linear programming approach for bi-objective optimization of biochemical systems has been presented.
The considered bi-objective problem should be concerned with the maximization of the production ux and the simultaneous minimization of the total metabolite concentrations. The S-system representation is easily transformed into a linear
model in logarithmic coordinates. Therefore, the optimization problem can be solved very efciently by means of linear programming. Proting from this property of S-system models, we have proposed a new strategy to transform the bi-objective
optimization problem into a mono-objective linear problem. The new algorithm is easily to be implemented within the linear programming techniques. The proposed framework has been applied to the fermentation pathway in S. cerevisiae. Compared with the mono-objective optimization results attained in the literature, a signicant improvement in metabolic cost J2,
transition time s and metabolic performance w can be obtained through the use of the proposed approach. These simulation
results show the tractability and effectiveness of the approximated linear programming in handling the bi-objective optimization of nonlinear biochemical systems.
Acknowledgments
This work was supported by the National Natural Science Foundation of China (Nos. 11101051 and 61070242), Liaoning
Province Doctor Startup Fund of China (No. 20101001) and Liaoning Provincial Natural Science Foundation of China (No.
20102003).
Appendix
The following ux rates in [33,34] are taken within the MichaelisMenten formalism:

V in Y 1  3:7X 2 ;
V HK

V PFK

A1

Y2
6:2104
X1 X5

0:11
X1

0:1
1
X5

50Y 3 X 2 X 5 R1
R21 3342L21 T 21

A2

A3

R1 1 0:3X 2 16:67X 5 50X 2 X 5 ;

L1

1 0:76AMP
;
1 40AMP

A4
A5

T 1 1 1:5  104 X 2 16:67X 5 0:0025X 2 X 5 ;

A6

q

1
ADP
12X 5  3X 25  X 5 ;
2

A7

AMP 3  X 5  ADP;

A8

V Pol

1:1Y 6
1:1
1 X22 8:25 0:7X
2:43
2

A9

G. Xu / Applied Mathematics and Computation 218 (2012) 75627572

7571

V GAPD

Y4
;
X5
0:18
AMP
ADP
NADH
1 0:25

2:5
1 0:25
1 0:0003

X3
1:1
1:5
X3
NAD

A10

NAD

2
;
Y9 1

A11

NADH

2Y 9
;
Y9 1

A12

V PK

Y 5 X 4 ADP2:519R2 0:656T 2 L22

1:0832R22 164:084L22 T 22

A13

R2 1 125:94X 4 0:2ADP 2:519X 4 ADP;

A14

T 2 1 0:02X 4 0:2ADP 0:004X 4 ADP;

A15

L2

1 0:05X 3
;
1 5X 3

A16

Y7
V PK ;
Y5

A17

V Gol

V ATPase Y 8 X 5 :

A18

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