1. Introduction
Gene expression is the process where the hereditary code of a gene is used for synthesizing proteins and producing the structures of the cell. Genes that code for amino acid sequences are named ‘structural genes’. Gene expression processes include two main stages known as ‘Transcription and translations’. Transcription is the creating of messenger RNA (mRNA) by the enzyme RNA polymerase and the processing of the resulting mRNA molecule. A gene regulatory network consists of a number of genes interacting by proteins. Mathematical models of gene regulatory networks are described and studied in several papers (see, for example, [
1,
2], for fractional order [
3,
4,
5,
6], and with delays [
7,
8]).
Recently, fractional calculus, fractional derivatives, and fractional integrals of various types have been extensively studied and applied in mathematical modeling. The memory property of fractional derivatives makes them well suited in modeling and describing the complex nature of real-world problems, in comparison to local derivatives (see, for example [
9,
10,
11]).
In this paper, a gene regulated model with the generalized proportional Caputo fractional derivative is set up, and the equilibrium is defined. The generalized exponential stability is introduced and studied via the application of Lyapunov functions and their generalized Caputo proportional fractional derivatives. Generalized proportional Caputo fractional derivatives were recently introduced (see [
12,
13]); this type of derivative is a generalization of the Caputo fractional derivative, and their application provides wider possibilities for modeling adequately the complexity of real-world problems. The stability of fractional order systems with a proportional Caputo fractional derivatives is quite recent (see, for example, [
14,
15]). In this paper, some properties of absolute values of Lyapunov functions and their fractional derivatives are discussed, and several examples are provided to illustrate the properties. The advantages of the application of the quadratic Lyapunov functions are considered, and sufficient conditions for generalized exponential stability and asymptotic stability are obtained. Several examples are provided to illustrate the theoretical results and the dependence of the fractional derivative on the behavior of the solutions.
2. Notes on Fractional Calculus
We recall the definitions needed in this paper, namely fractional integrals and derivatives (cf. [
13]):
The generalized proportional fractional integral of a function
is defined by (as long as all integrals are well defined)
The generalized Caputo proportional fractional derivative of a function
is defined by (as long as all integrals are well defined)
where
.
Remark 1. Note that the generalized proportional Caputo fractional derivative is defined for via component-wise.
Remark 2. If , then the generalized Caputo proportional fractional derivative reduces to the classical Caputo fractional derivative of order Definition 1. We say if is differentiable and the generalized proportional Caputo fractional derivative exists for all .
Lemma 1. Let . Then, the generalized proportional fractional derivative of a constant is Proposition 1. ([13], Remark 3.2) The relationholds. We will use the following property of the Mittag–Leffler function with one parameter, defined by with the gamma function.
Proposition 2. ([16], Theorem 1.2) For every , the function is completely monotonic. Corollary 1. [16] If , then . 4. Statement of the Problem
In this paper, we will consider a class of fractional order gene regulatory networks modeled by a generalized proportional Caputo fractional derivative for
,
:
where
,
denote the concentrations of messenger ribonucleic acid (mRNA) and protein of the
j-th node at time
t, respectively,
and
are degradation velocities of mRNA and protein, respectively,
is the translation rate, the functions
represent the activator initiates of protein of mRNA, and the coupling matrix of the network
is described by
and
, where
is the set of all repressors of gene
j.
Remark 8. Commonly, the activator functions are indicated in the Hill form , where are the Hill coefficients and are constants.
Remark 9. Note that the model (9) is studied in the case of the Caputo fractional derivative and the absolute value Lyapunov function is applied (see Remark 4). Introduce the following assumptions:
(A1) The activator functions
are increasing and there exist constants
such that for any
with
the inequalities
hold.
(A2) There exist positive constants
such that the coefficients in (
9) satisfy the inequalities
Remark 10. From Assumption (A1), it follows that Lemma 2 is applicable to the solutions of (9) and equality (7) holds; i.e., the absolute value Lyapunov function is applicable to (9). From Lemma 1, it follows that the generalized proportional Caputo fractional derivative of a nonzero constant is not zero, and applying Corollary 1, we introduce the following definition.
Definition 2. The couple of functionswith , is called an equilibrium of (9) if Remark 11. Note that in the case of Caputo fractional derivative (), the defined equilibrium in Definition 2 coincides with the one known in the literature (see, for example, [3]). Definition 3. The equilibrium of the model (9) is generalized exponentially stable if there exist constants such thatwhere is the solution of (9) with initial values . Then, (
9) can be written in the form
where
The system (
11) has a zero equilibrium.
The goal of our paper is to study the exponential and asymptotic stability of the equilibrium of (
9); equivalently, we also study the stability properties of the zero solution of the IVP for FrDE (
11).
We will apply quadratic Lyapunov functions, and in connection with this, we will use the following result:
Lemma 4. ([14], Lemma 2) Let the function , with be a solution of (11), and suppose that, for any , the inequalityholds. Then,where Lemma 5. ([14], Lemma 3) Let the function , with , be a solution of (11) and suppose that, for any , the inequalityholds, where is a constant. Then,where Theorem 1. Let the assumptions (A1) and (A2) be satisfied, and assume that there exists an equilibrium of the model (9). Then, the equilibrium of the model (9) is generalized exponentially stable. Proof. The generalized exponentially stability of equilibrium of the model (
9) is equivalent to the generalized exponential stability of the zero solution of (
11).
Consider the Lyapunov function
where
Let
be a solution of (
11). According to Lemma 3, we obtain
From assumption (A2), it follows that
and thus
where
According to Lemma 5, the inequality
holds, where
and
or
□
Corollary 3. Let the conditions of Theorem 1 be satisfied. Then, the equilibrium of the model (9) is asymptotically stable, i.e., 5. Applications
Application 1
We will consider the model of three repressor-protein concentrations,
, and their corresponding mRNA concentrations,
, which are defined and studied in [
21] when the kinetics of the system are determined by ordinary differential equations. To have a more appropriate model, we will adopt this model and use generalized proportional Caputo fractional derivatives; i.e., we will consider the model
where (see [
21]):
- -
The number of protein copies per cell produced from a given promoter type during continuous growth is in the presence of saturating amounts of repressor and in its absence;
- -
is the ratio of the protein decay rate to the mRNA decay rate;
- -
n is a Hill coefficient.
System (
19) is similar to (
9) with
,
,
and
for
,
.
Take
and
. Thus,
,
, and
and
i.e., assumptions (A1) and (A2) are satisfied. According to Theorem 1, if there exists an equilibrium
of (
19), then it is generalized exponential stable.
Case 1.
Caputo fractional derivative, i.e.,
. The equilibrium
is a solution of the system
The system (
20) has a solution for every value of
and
.
Consider a particular case of and . Then, the equilibrium is .
The solutions
are given in
Figure 2 (left), and the solutions
, are given in
Figure 2 (right). It could be seen that all components of the solution approach the equilibrium
.
Note that problem (
19) is considered in [
3] with
. However, in this case, the equilibrium is
, which does not correspond to the provided graphs.
Let . Then, the equilibrium is .
The solutions
are given in
Figure 3 (left) and the solutions
, are given in
Figure 3 (right). It could be seen that all components of the solution approach
.
Case 2. Generalized proportional Caputo fractional derivative, i.e., .
Since
and
, the equilibrium
is a solution of the system
Case 2.1. Let
. Then, the system (
21) has zero solution w.r.t.
and the system (
19) have a zero equilibrium. The solutions
are given in
Figure 4 (left) and the solutions
are given in
Figure 4 (right). It could be seen that all components approach the equilibrium 0.
Case 2.2. Let
. Then, the system (
21) has no solution w.r.t.
, and the system (
19) has no equilibrium, and we could not apply Theorem 1.
Application 2
Consider the model of three repressor-protein concentrations,
, and their corresponding mRNA concentrations,
, (
19) with the activator functions
; i.e., consider
with
. The system (
8) has a zero equilibrium. Take
and
. Thus,
,
and assumptions (A1) and (A2) are satisfied. According to Theorem 1, the zero equilibrium is generalized exponential stable. The graphs of the solutions
and
, of system (
22) are given in
Figure 5 (left) and
Figure 5 (right), respectively, with
,
,
,
,
, with initial values
.
Application 3
Consider the general model describing the dynamics of the interacting defects in the genome and in the proteome with the generalized proportional fractional derivative:
where
is the coupling rate constant characterizing the regulation of gene expression by the proteins,
K is the average number of genes regulated by any single protein and represents a simple measure of the overall connectivity of the genetic network,
c reflects the combined efficiency of proteolysis and heat shock response systems, mediating the degradation and refolding of misfolded proteins, respectively, whereas
characterizes the DNA repair rate, the “force” terms,
and
characterize the proteome and genome damage rates, respectively, and
G is the total genome size.
Let
and
. Then, the model (
23) has equilibrium
Model (
23) is in the form of (
9) with
,
,
,
. Thus,
,
and
and
i.e., assumptions (A1) and (A2) are satisfied if
and
. In other words, the DNA repair rate
and the expressome (proteome, metabolome) turnover rate,
c, have to be large enough. In
Figure 6, the graphs of the solution
are given with
,
, and the initial values
,
. Then, the equilibrium is
Note that the model (
23) in the case of ordinary derivatives is studied in [
2] with the more restrictive assumption
.