TOPICS ON COMPUTATIONAL BIOLOGY AND CHEMISTRY

Mathematical and computational modeling of biosensors:

Modeling for enzyme-substrate interaction and biomolecular
interaction
Yupeng Liu Qi Wang
Dublin Institute Technology Dublin Institute Technology
School of mathematical sciences School of mathematical sciences
Kevin Street, Dublin 8 Kevin Street, Dublin 8
Ireland Ireland
yupeng.liu@dit.ie qi.wang@dit.ie

Abstract: The main components of biosensors are based on well-understood physical processes (such as diffusion,
convective flow, energy and mass transfer) as well as chemical and biological reactions, all of which are amenable
to differential equations. Using mathematical and computational modeling techniques to characterize the biosen-
sor response as a function of its input parameter in wide range of physical contexts, it can guide experiments,
therefore reducing development times and costs. In this paper we investigate the problem of optimizing biosensor
design using an interdisciplinary approach which combines mathematical and computational modeling with elec-
trochemistry and biochemistry techniques. Specifically, a model for enzyme-substrate interaction and a model for
biomolecular interaction will be developed and used as building blocks towards describing more complex electro-
chemical immunoassay systems. The ultimate goal is to develop a flexible, modular mathematical model, which
can be used towards a software platform capable of predicting the behavior of a wide range of electrochemical and
optical biosensor.

KeyWords: Biosensor, electrochemical biosensor, enzyme-substrate kinetics, biomolecule interaction, diffusion

equations, boundary conditions, numerical simulations.

1 Introduction called the enzyme substrate complex C, etc. Enzyme

Biosensors are analytic devices which detect bio-
chemical and physiological changes and represent an
emerging technology for low-cost, rapid and simple
to operate biomedical diagnostic tools. Biosensor has
become very significant to our daily life in many ar-
eas, hometesting devices for many diseases and dis-
orders, measuring water quality, presenting the harm-
ful micro organisms in food etcs. Biosensor design
underpins the development of a range of next gener-
ation biomedical diagnostic tools which will directly
affect the quality of life worldwide over the next few
decades. The most widely used biosensors are en-
zyme interfaced biosensors and optical biosensors.
Optical biosensors usually involves biomolecular in-
teraction, they are very often used for affinity relation
test.
2 Enzyme substrate interaction
The catalytic event that converts substrate to product
involves the formation of a transition state. The com-
plex, when substrate S and enzyme E combine, is
interfaced biosensors involves enzyme-substrate inter-
action, two significant applications are: monitoring of
human glucose and monitoring biochemical reaction
at a single cell level. Normally, we have two ways to
set up experiments for biosensors: free enzyme model
and immobilized enzyme model. The mathematical
and computational model for these two models are
very similar, at here we are going to investigate the
free enzyme model.
2.1 Free enzyme model
This model will be used to analyze the reaction rates
of species diffusing together. The difference between
free enzyme model and immobilized enzyme model
is the reactions of free enzyme model are not tak-
ing place on the electrode surface. The enzymes are
placed in the test tube with substrates diffuse through
out the test tube. The substrates will react with the
enzymes at t = 0. As they react, the species C and
P will be formed. These species will diffuse to the
electrode at t > 0. It is at point (x = 0) that current
measurements can be taken. The reaction follows the

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 TOPICS ON COMPUTATIONAL BIOLOGY AND CHEMISTRY

Michaelis-Menten scheme. C 2C
= Dc (K1 + Kcat )[C] + K1 [E][S] (7)
T X 2
k1 k
cat
E + S  C E +P (1) Zero-flux boundary conditions are:
k1
S P
where P is the reaction product, the constants k1 , k1 Ds (L, t) = 0 Dp (L, t) = 0 (8)
x x
and k2 represent the rates of reactions.
E C
De (L, t) = 0 Dc (L, t) = 0 (9)
2.2 Construct mathematical equations for x x
free enzyme model S P
Ds (0, t) = 0 Dp (0, t) = 0 (10)
At t < 0 the substrate fixed to the top of the test tube. x x
At t = 0 both species are released by a conduction E C
De (0, t) = 0 Dc (0, t) = 0 (11)
medium and it starts diffuse throughout the tube. x x
When the diffusion medium R is a bounded Initial conditions are:
domain in V , the reaction diffusion equations are
supplemented by suitable boundary conditions on the P (x, 0) = 0 E(x, 0) = E(0) C(0) = 0
boundary surface S. The appropriate conditions on (12)
the boundary depends on the physical mechanism sur-
rounding the diffusion medium. Often the conditions From law of mass conservation, we have E = E0 C,
on the boundary depends on the material properties where E is the total amount of enzyme present on the
both inside and outside the diffusion medium. electrode and S0 (x) = S0 if x = L and 0 otherwise.

When the flux across the boundary surface is pre- 2.3 Simulation results of free enzyme model
scribed, the boundary condition becomes
2.3.1 Simulation results for Substrate
u
= h(x, t) (2) After solve the partial differential equations that de-
v fine the experiment by using finite difference scheme.
where h represents the rate of flow of the density and Shown below is the numerical output for the substrate.
u/v is the directional derivative of u in the direc- Fig.1 shows the diffusion of the substrate in the con-
tion of v. What is more relevant to this paper is the duction medium.
homogeneous Neumann boundary condition
u
=0 (t > 0, x S) (3)
v
The physical meaning of this equation is that the
boundary surface is completely insulated so that there
is no flux across the boundary, (known as the zero flux
boundary condition). In the context of our models this
boundary condition will be used on the free surface of
the diffusion medium as the chemical species cannot
leave the solution.
We now construct the differential equations from
the principle of conservation which governing the be-
havior of the relevant chemical species. The substrate
hydrogen peroxide is free to diffuse throughout the Figure 1: Substrate
domain, hence
It can be seen from Figure 1 that initially at t = 0
S 2S the substrate is concentrated in an area around x = L.
= Ds + K1 [C] K1 [E][S] (4)
T X 2 This corresponds to the initial condition applied the
experiments. At t = 0 it diffuses from a area of
P 2P high concentration into an area of low concentration.
= Dp + Kcat [C] (5)
T X 2 In doing so it diffuses to the electrode where the
E 2E substrate reacts with the enzyme to form a compound.
= De + (K1 + Kcat )[C] K1 [E][S] (6)
T X 2

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 TOPICS ON COMPUTATIONAL BIOLOGY AND CHEMISTRY

Also at the electrode surface (x = 0), we can see

that it takes time for the substrate to diffuse across to
electrode. This is notable in the beginning seconds
of the experiment. After a short while the substrate
is being consumed at a faster rate than the reversible
chemical reaction, of the compound, the substrate
eventually approach zero as it is converted to product.

2.3.2 Simulation results for Enzyme

Shown below is the numerical results of the reaction

diffusion equations that describe the rate of change of
enzymes. Fig.2 shows the enzyme diffusing across
the conduction medium from an area of high concen-
tration (at t = 0) to an area of low concentration. The
concentration of enzyme at the electrode rises sharply
at the beginning due to the diffusion. We have shown
in the Michaelis-Menten analysis that the concentra-
tion of enzyme is conserved in a reaction and at any
point in time, its concentration can be deduced by the
fact thatE0 = E +C. This can be tested by comparing
both figures Fig.2 and Fig.3.
Figure 3: Compound
2.3.4 Simulation results for Product
Shown below is the simulation result for the product.
It can be seen in Fig.4 that the initial concentration of
product is zero, which is one of the initial conditions
applied to the experiment. Since the product depends
on the formation of compound, the products form in
high concentrations in early time intervals.

Figure 2: Enzyme
Figure 4: Product

2.3.3 Simulation results for Compound

Shown below is the simulation result for the com-

pound. Fig.3 shows that the compound initially forms
in high concentration around the region x = L. This
is due to the initial conditions set in the experiment.
The compound then diffuses to an area of lower
concentration to reach an equilibrium state.
3 Biomolecule model
Biomolecular interactions is a central element in un-
derstanding disease mechanisms and is essential for
devising safe and effective drugs. Optical biosensors
usually involves biomolecular interaction, they are
very often used for affinity relation test.

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Figure 5: BIACORE
3.1 Mathematical modeling for Antibody-
Antigen interations
The reaction between antibodies and antigens do not
release electrons. This type of model is more ap-
propriate for a different type of biosensor, a Quartz
Crystal Resonator. It is widely used in various kinds
of electronic equipments and measurement instru- Figure 6: BIACORE flow channel
ments, such as cordless telephone and broadcasting.
This model will involve a basic reaction with antigen
(y = h) and bottom (y = 0) boundaries, and max-
and antibody. Their experiment involves placing the
imal and equal to vc in the centre (y = h/2). The
species in a rectangular shaped test tube. The antibody
velocity v(y) at a height y above the sensor surface is
will be immobilized at the electrode and the antigen
will diffuse to the electrode to form a product. The y y
reaction scheme and mathematical models are shown v(y) = 4vc ( )(1 ) (20)
h h
below
K1
Ab + At P (13) In the flow channel, the analyte concentration
C(t, x, y) is governed by the following equation
[At ] 2 [At ]
= Dat (14)
T X 2
C 2C 2C y y C
[At ] = D( 2 + 2
) 4vc ( )(1 ) (21)
(L, T ) = 0 (15) t x y h h x
X
[At ] with boundary conditions:
Dat (0, T ) = K1 [At ][Ab ] (16)
X
C(t, x, y)
d[Ab ] = 0 at y=h (22)
= K1 [At ][Ab ] (17) y
dT
dP
= K1 [At ][Ab ] (18) C(t, x, y) B(t, x)
dT D = at y=0 (23)
y t
[Ab ](0) = [Ab ]o , [P ](0) = 0 (19)
B(t, x)
= ka C(t, x, 0)R(t, x)kd B(t, x) at y=0
3.2 Mathematical modeling for BIACORE t
(24)
The BIACORE (Fig.5) is an optical biosensor spe-
C(t, x, y) = CT at x=0 (25)
cializing in measuring protein-protein interaction and
binding affinity. The technology is based on surface C(t, x, y)
plasmon resonance (SPR), an optical phenomenon = 0 at x=l (26)
x
that enables detection of unlabeled interactants in real
time. C(t, x, 0) is the free analyte concentration at time t
The velocity profile in the y direction does not and position x, just above the sensor surface. B(t, x)
vary over most of the width of the chamber (Figure is the concentration of bound analyte-receptor com-
6), the boundary at the chamber walls where the ve- plex on the cell surface and R(t, x) = RT B(t, x) is
locity drops to 0 extend less than h/w of the channel the free surface receptor concentration. RT is the total
width. Also we take the flow to be fully developed receptor concentration, which is constant with respect
throughout the flow cell, so that the velocity profile to both position and time. The rate constants for the
is parabolic for 0 x l, equal to zero at the top reaction are ka and kd .

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 TOPICS ON COMPUTATIONAL BIOLOGY AND CHEMISTRY

4 Conclusion
As we can see from the simulation results for
free enzyme model, the simulation is as what we
expected. After comparing the simulation results
with the experimental results which obtained from
the chemists in NCSR (National Centre for Sensor
Research), the simulation of free enzyme model
accurately describes the experiments. By using this
simulation model we could find the most efficient
ratio between enzyme and substrate and equilibrium
states. Similarly, we could generate the simulation
results for the biomolecular model by numerically
solve the system of partial differential equations we
generated base on the reaction.

This proves that mathematical and computational

modeling can be used for biosensor design to predict
behaviour, validate the theory and to guide experimen-
tal work.

Acknowledgements: The authors would like to

thank the Irish Research Council for Science, Engi-
neering and Technology and The Mathematics Appli-
cations Consortium for Science and Industry for their
support.

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