Kinetic Model of Enzyme Biosensor: Analytical and

Numerical Studies with COMSOL Multiphysics

Elbahi Djaalab1, Mohamed El Hadi Samar1, Saida Zougar1 And Rochdi Kherrat1
1
Department of Process Engineering, Faculty of Engineering Sciences, Badji Mokhtar Univer-
sity-Annaba, Algeria.
djaalabahi@gmail.com

Abstract. In the present paper, the mathematical model of enzyme biosensor

contain immobilized enzymes with spherical geometry have been developed.
By applying changing variables method, to solve the coupled nonlinear steady-
state reaction - diffusion equations for Michaelis-Menten kinetic that describes
the concentrations of substrate and product within the enzymatic layer. The ana-
lytical expressions for concentration of substrate and product have been derived
for all values of rate constant. A numerical simulation is also reported using
COMSOL Multiphysics software program. Our analytical results are compared
with our simulation results. The obtained results have a good agreement with
those obtained using numerical method. The principal factor controlled
catalytical response Damkohler number have been studied.

Keywords: Modeling, Enzyme, Biosensor, Reaction-Diffusion, COMSOL.

Abbreviations
PDE Partial differential equations (PDE)
E Enzyme (E)
S Substrate (S)
ES Enzyme-substrate complex (ES)
P Product (P)
Molar concentrations of the substrate in the enzyme layer
Molar concentrations of the product in the enzyme layer
and The diffusion coefficients.
r Space between 0 and radius R
The maximal enzymatic rate;
The Michaelis constant;
S(r) Dimensionless concentration of substrate s
P (r) Dimensionless concentration of product p
2

1 Introduction

A mathematical model is a description of a system using mathematical concepts

and language (Ingham et al. 2008). The process of developing a mathematical model
is termed mathematical modeling. Mathematical models are used in the natural sci-
ences (Neimark 2012; Alvarez and Illman 2005) and engineering disciplines (Castillo
et al. 2011; Luyben 1989; Kulov and Gordeev 2014). A model may help to explain a
system and to study the effects of different components, and to make predictions
about behaviour (Wrzosek et al. 2013). Mathematical models play a vital role in en-
zyme biosensor application (Djaalab et al. 2018).
Computer simulation has become an essential field of science and engineering
(Buzzi-Ferraris and Manenti 2013; Ross 1987). Modeling has a spectrum of applica-
tions, which range from concept development and analysis, through experimentation
(Illeová 2003), measurement and verification, to disposal analysis application. Pro-
jects and programs may use hundreds of different simulations, simulators and model
analysis tools (Elnashaie and Uhlig 2007; Martín 2014).
COMSOL Multiphysics is an interactive environment for modeling and solving all
kinds of scientific and engineering problems (Pryor 2009, 2015; Zimmerman 2006;
Zhang and Cen 2015; Tabatabaian 2015). The software provides an integrated desk-
top environment with a Model Builder where you get full overview of the model and
access to all functionality. With COMSOL Multiphysics, conventional models for one
type of physics can be extended into Multiphysics, models that solve coupled physics
phenomena and do so simultaneously (Dokos 2017; Arriaga et al. 2008).
In chemical engineering, modeling and simulation are important tools for engineers
and scientists to design, to optimize pieces of equipment (Ingham 2000). Modeling
and simulation are extremely important tools in the chemical sciences for understand-
ing and engineering of complex chemical processes, such as enzymatic biosensors.
Enzymatic biosensors based on polymerized films constitute an important field of
analytical chemistry (Sassolas et al. 2012; Bučko et al. 2012). Enzymes interact spe-
cifically with some substrates, and can thus be used for the detection of these sub-
strates.
Mathematical models of enzyme biosensor response can be modeled by solving par-
tial differential equations (PDE) of the reactive diffusion and the catalytical conver-
sion with the initial and the boundary conditions (Baronas et al. 2009; Loghambal et
al. 2011; Manimozhi et al. 2010). Theoretical modeling time independent non-linear
differential equations for the chemical reaction implies the use of a nonlinear term
related to first order kinetic scheme can be solved analytically and numerically. For
this purpose, this paper is to derive an analytical expression for concentration of reac-
tive and product for application in biosensor field.
Objective of the present investigation is to develop a model with analytical model-
ing tool for enzyme biosensor process with spherical geometry. We try to simulate a
model, which can be used for simulation of the reaction and mass transfer in enzyme
film. Approximating equations concerning the substrate and product properties are
used in modeling process, we try in this work to develop the mathematical model with
COMSOL Multiphysics modeling tool.
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2 Kinetics and Mathematical Model

2.1 Kinetics Model

The kinetic model for an enzyme biosensor action, first elucidated by Michaelis and
Menten (Eq. (1)) suggested the binding of free enzyme (E) to the reactant or Substrate
(S) forming an enzyme-substrate complex (ES). This complex undergoes a transfor-
mation, releasing the product (P) and enzyme (E). Note that substrate binding is re-
versible but product release is not. (Figure 1).
Henri postulated the following scheme of enzyme biocatalyzer action in 1902
(Baronas et al. 2009):

Practically, the enzyme reaction can be considered first-order when the concentration
of the detected species is below one-fifth of KM, (Baronas et al. 2009).
This case is rather typical for the biosensors with a high enzyme-loading factor.
The nonlinear reaction–diffusion system (7) reduces to a linear one,

P
S
S P
Enzyme P
S
S
P

Diffusion : Reaction :

Enzyme layer

S P

Fig. 1. Kinetic reaction diffusion in biosensor process with immobilize enzyme.

2.2 Mathematic Model of spherical catalysis

In biosensor, coupling of substrate transport with diffusion described by Fick’s law
with the enzyme-catalyzed reaction in the enzyme layer, leads to the following equa-
tions:
4

Where r stands for space between 0 and radius R; and are the molar con-
centrations of the substrate and the product in the enzyme layer, respectively;
is the maximal enzymatic rate; is the Michaelis constant; and are the diffu-
sion coefficients.
For enzyme biosensor field, the amount of substrate is small, we able that: The
amount of the substrate is negligible compared to the amount of The Michaelis
constant, . Then, the equations (3) and (4) will be reduced to the following form:

With

2.3 Dimensionless Form of the Problem

At this point, we can obtain better insight by converting the problem into dimen-
sionless form. Equation 4 and 5 has two dimensional quantities, length and concentra-
tion.
The only concentration appearing in the problem is the surface concentration in the
boundary condition, so we use that quantity to non-dimensionalize the concentration

With
 5

3 Analytical solution of kinetic of spherical catalysis

3.1 Rearrange Equations with Modified Variable

The following parameters are used to convert the above Equations 7 and 8 into nor-
malized form. We make the above nonlinear partial differential equations in dimen-
sionless form by defining the following parameters:

The Equations 7 and 8 reduce to the following dimensionless form:

The dimensionless initial and boundary conditions are:

3.2 Analytical solution of kinetic of substrate concentration:

The partial differential equation (10) of substrate :

With boundary conditions:

General solution of this equation:

6

With boundary conditions at = 0 and =1, the solution of these is:

Dimensionless solution

Final solution of substrate concentration:

3.3 Analytical solution of kinetic product concentration

After addition Eq. (10) to Eq. (11):

We need to introduce new function :

We obtain a system of ordinary differential equation:

With

The analytical solution of Eq. (21) with initial and boundary Eq. (22) in the form:
 7

By using Eq. (11), Eq. (20) and Eq. (23), we get

Dimensionless solution of product:

After rearrangement, solution of product concentration given by:

4 COMSOL Multiphysics modeling

4.1 Coefficient Form, Interpretations

With equation-based modeling, part of the core functionality of COMSOL
Multiphysics, you can create your own model definitions based on mathematical
equations.

To implement Eq. (7) and Eq. (8) in COMSOL Multiphysics, we use the Model Wiz-
ard to create a new 1D model with a Form PDE interface (under Mathematics > PDE
Interfaces) and a Stationarystudy. The dependent variable can be set to u to match the
notation in our equation. For the geometry, we make an Interval between 0 and 1.

4.2 Modeling Instructions

a. Model Wizard
. . . Start Comsol Multiphysics.
To start Comsol Multiphysics 5.2 open the Terminal and enter
• comsol -ckl
8

Model Wizard.
Space dimension
• In the New window, click Model Wizard.
• In the Model Wizard window, click 1D in the Select Space Dimension menu.
Equation
• In the Select Physics tree, select Mathematics>PDE Interfaces>Coefficient
Form
PDE (c).
• Click Add.
• Next, locate the Dependent Variables section.
• In the Field name text field, type u.
• In the Dependent variables text field, type also u.
Study settings
• Click Study and choose Preset Studies > steady state.
• Click Done.

b. Geometry
. . • In the Model Builder tree, expand the Component 1 (comp1) node, right-click
Geometry
1 and select Interval.
• In the Settings window for Interval, locate the Interval section.
• In the Left endpoint text field, type 0.
• In the Right endpoint text field, type 1.
• In the Model Builder tree, right-click on the Component 1 (comp1)→Geometry 1
node and select Build all. (Alternatively, press the short cut F8.)

c. General Form PDE

 . . . Click PDE.
 Click Dependent.
Type in Number of dependent variables: 1.
Type in Concentrations: u.
 Click PDE.
 Click General Form PDE
 Right click PDE and select Dirichlet Boundary Condition 1.
Right-click Coefficient Form PDE and choose Dirichlet Boundary Condition.
Select Boundary 1 only
 Right click PDE and select Dirichlet Boundary Condition 2.
Right-click Coefficient Form PDE and choose Dirichlet Boundary Condition.
Select Boundary 2 only

d. Mesh
..
 In Element size menu choose Extra fine. If accurate results required
mesh size should be significantly smaller than any geometrical fea-
ture or feature in the solution.

e. Solver Settings
..
 9

Once the solver settings have been specified, right-clicking the study node and se-
lecting Compute (=) will solve the model. Solution progress can be examined in the
Progress Information window.
10

5 Result and Discussion

5.1 Analytical solution validation

The analytical solutions are validated for specific set of values. In this work, the ana-
lytical data are validated through numerical data obtain from numerical simulation
with COMSOL Multiphysics. The function PDE in COMSOL Multiphysics software,
which is a function of solving the initial boundary value problems for parabolic partial
differential equations, is used to solve the Eq. (7) and Eq. (8) for the corresponding
boundary conditions Eq. (9).
The Fig. 2 and Fig. 3 shows response of spherical catalysis for various reactive and
product concentrations, accepting, the case a=10 with different initial concentration
= 2, 4, 6, and 10. In all the cases, the percentage of deviation of analytical solution
from numerical result is calculated that is less than 1%. It conforms that, the modeled
data with analytical solution are very much similar to COMSOL Multiphysics data.

Fig. 2. Comsol modeling response of enzyme biosensor substrate with a=10

 11

Fig. 3. Comsol modeling response of enzyme biosensor product with a=10

5.2 Reaction – Diffusion effect

The mathematical model presented here in Eq. (18) for substrate and Eq. (26) for
product utilizes well-developed nonstructural spherical metal -catalyzed reaction dif-
fusion equations, which were applied to kinetic catalysis. Mathematical solution result
in Eq. (18) and Eq. (26) indicate that: factor is the principal factor con-
trolled cataltical response.

When the Damkohler number is large, internal diffusion usually limits the overall
rate of reaction; when Damkohler number is small, the surface reaction is usually
rate-limiting.

Fig. 4 and Fig. 5 shows the concentration profile for different values of Damkohler
number. Small values of the Damkohler number indicate surface reaction controls and
a significant amount of the reactant diffuses well into the membrane without reacting.
12

Fig. 4. Reaction diffusion effect of substrate concentration when =4.

We found from the Fig. 4 that with decrease in the Damkohler number there is an
increase in the dimensionless substrate concentration degradation. From the Fig. 5,
concentration of the product decreases, when there is a decrease in the Damkohler
number

Fig. 5. Reaction diffusion effect of product concentration when =4.

 13

6 Conclusion

The mathematical model of kinetic biocatalysts enzyme with spherical structure can
be successfully used to investigate the response of catalytic effect when surface cata-
lytic reacts with its reactive to produce new product. The approximate analytical ex-
pression of substrate and final product has been derived using spherical coordination
with variable change to solve the coupled nonlinear time-independent reaction - diffu-
sion equations for describes the concentrations of reactive and product within the
catalytic enzyme film. Our results are compared with the numerical simulation with
COMSOL Multiphysics software program. A good agreement is noted between ana-
lytical and numerical results. The analytical method is an extremely simple method
and it is promising method for the better understanding of spherical biocatalytical
enzyme model in biosensor field.

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