BioSystems 91 (2008) 489498

Available online at [Link]

Biological networks in metabolic P systems
Vincenzo Manca

, Luca Bianco
University of Verona, Department of Computer Science, Strada Le Grazie 15, 37134 Verona, Italy
Received 30 March 2006; received in revised form 24 October 2006; accepted 29 November 2006
Abstract
The metabolic P algorithm is a procedure which determines, in a biochemically realistic way, the evolution of P systems repre-
senting biological phenomena. A new formulation of this algorithm is given and a graphical formalism is introduced which seems to
be very natural in expressing biological networks by means of a two level representation: a basic biochemical level and a second one
which regulates the dynamical interaction among the reactions of the rst level. After some basic examples, the mitotic oscillator
in amphibian embryos is considered as an important case study. Three formulations of this biological network are developed. The
rst two are directly derived by Goldbeters differential equations representation. The last one, entirely deduced by translating the
biological description of the phenomenon in our diagrams, exhibits an analogous pattern, but it is conceptually simpler and avoids
many details on the kinetic aspects of the reactions.
2007 Elsevier Ireland Ltd. All rights reserved.
Keywords: P systems; Membrane systems; Metabolism; Biological networks; Biological oscillators; Biological discrete models
1. Introduction
One of the most important problems mathematicians
and computer scientists have to cope with, while mod-
elling biological phenomena, is a deep understanding
and a clear representation of the phenomena related
to intercellular or intracellular information transfer. In
fact, in the analysis of the interactions occurring in
metabolic or signal pathways, very complex networks
are expressed, in their specic mechanisms, by terms
like synthesis, production, catalysis, degradation, intro-
duction, expulsion, consumption, inuence, activation,
inactivation, inhibition and promotion. Many of these
concepts have a simple translation in formal terms,
but other are very often vague, ambiguous, or strongly
depending on the specic contexts in which they are

Corresponding author.
E-mail addresses: [Link]@[Link] (V. Manca),
bianco@[Link] (L. Bianco).
embedded. The graphical notations which are used in
the visualizations of these networks (Segel and Cohen,
2001; Voit, 2000) have only an intuitive basis and when
one attempts to express themin mathematical terms, then
many inconsistencies or confuse meanings are easily
encountered; moreover, they do not provide information
about the dynamics of the network they represent. There-
fore, a natural question arises: is it possible to reduce
the most important biological regulation mechanisms
to some basic relationships which could permit rigor-
ous mathematical translations? In this paper, we present
some initial steps along this direction. In fact, a nota-
tion for representing some biological networks is here
described which is related to the metabolic algorithm
(Bianco et al., 2006a, b; Fontana et al., 2006; Manca et
al., 2005), an effective method for computing biolog-
ical dynamics we have developed in the framework of
P systems (P aun, 2000, 2002). This notation provides
not only the basic information of the biochemical reac-
tions, but it also gives the reaction regulation functions
which are the core of metabolic algorithmfor computing
0303-2647/$ see front matter 2007 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/[Link].2006.11.009
490 V. Manca, L. Bianco / BioSystems 91 (2008) 489498
the dynamics of a special class of biologically meaning-
ful P systems. One of the main purposes of Systems
Biology, is to understand the dynamic and molecular-
level relationships among biological molecules in living
systems. For this reason, tools which provide intu-
itive ways for representing and analyzing the dynamics
of complex biological networks seem to be a neces-
sary step in the assessment of a discipline that seeks
to nd the hidden structures underlying molecular
data.
2. The P Metabolic Algorithm
P systems are a computational model based on the
compartmentalization of the workspace and on multi-
set rewriting. These concepts were introduced due to
their strong biological motivation; in fact, they are intrin-
sically related to the basic role that membranes have
in biological organisms and in the biochemical basis
of any biological reality. In other words, the localiza-
tion and the concentrations of any biochemical element
at each instant determines all the relevant properties
which underlie the form and the function a biological
system exhibits at that time. We refer to P aun (2000,
2002) and the website at [Link]
for the denitions of P systems structure in all of the
most important variants and for the most typical strate-
gies which establish their evolution in time. However,
from a biological viewpoint, the strategies of evolution
considered in the standard P systems seem to be com-
pletely inadequate. In fact, the transition from a state
to the next one is usually given by a maximally par-
allel application of rules which determines the way of
transforming objects, of moving them from a mem-
brane region to another one and, in the more general
cases, of changing the topological setting of mem-
branes. But, maximal parallelism or other strategies of
this kind cannot express the dynamics of populations
of chemicals governed by biochemistry laws. There-
fore, we started with this main question: How does
a membrane system evolve in a biochemical realistic
sense? and, more specically, How is it possible to
nd a membrane system modelling some given biolog-
ical phenomena, by reproducing its observed evolution
in terms of concentration and localization of biochem-
icals?. In order to address these questions we dene
an evolution strategy, called Metabolic P Algorithm,
shortly MPA, which is a new formulation of algo-
rithms given by Bianco et al. (2006a, b), expressing
the essence of biochemical dynamics in a clearer and
more intuitive way. An interesting feature of MPA is
that it does not oblige to take a detailed account of the
exact biochemical kinetic of the system under investiga-
tion.
In the following, the main principles of this algorithm
are formulated in a way that is directly related to the
graphical formalism we present in the next section. For
the sake of simplicity, we consider the simple case of
only one membrane but, at the price of an heavier nota-
tional cost, the algorithm can be dened in the general
context of multi-membrane systems as well. The leading
principles of the MPA are the following:
Reactants are distributed among all the rules step by
step according to a competition strategy.
If different rules need the same reactant, then each of
these rules gets a portion of the available substance, in
a percentage that is proportional toits reactionstrength
(reactivity) at that step.
The reactivity of a rule at a given instant depends on
the state of the system, dened as the concentration
and localization of all substances.
According to its stoichiometric reading, any rule
determines its own reaction unit and therefore the
amount of substances which it consumes and pro-
duces.
We summarize these principles with four statements:
(1) Rules compete for object populations.
(2) Objects are allocated to rules according to a mass
partition principle.
(3) Partition factors are determined by reaction maps.
(4) A Metabolic rule r consumes/produces integer
multiples of a reaction unit u
r
which generalizes
the notion of molar unit (Avogadros principle).
An example may be useful to clarify these princi-
ples. Let T = {A, B, C, . . .} be an alphabet of biological
species (or types), we dene q : T N as the state of
the system, that is, the concentration of each type at a
certain observation instant. Assuming that, in a given
instant, four rules, say r
2
, r
3
, r
5
andr
7
, needmolecules of
a certain type A for performing some biochemical reac-
tions (see Fig. 1), then a partition strategy for species A
is necessary.
The novelty of our approach is that of considering, for
any state of the system, a real number as the strength of
any rule, which is the value assumed by a reactivity, or
reaction map, in the considered state. For example, with
respect to Fig. 1, if a, b, and c are the concentrations
of species A, B, and C, respectively, then the reactivities
associated to the rules r
2
, r
3
, r
5
and r
7
in a state q, which
V. Manca, L. Bianco / BioSystems 91 (2008) 489498 491
Fig. 1. Competition for object A.
ask for A molecules could be:
f
2
(q) = 200a, f
3
(q) = 0.5a
1.25
b
1
,
f
5
(q) = a
1.25
(b + c)
1
and f
7
(q) = 10.
We dene
K
A,q
=

i=2,3,5,7
f
i
(q)
as the total pressure on A. Then, for each of the compet-
ing rules r
j
we consider the partial pressure (or weight)
of r
j
on type A as
w
A,q
(r
j
) =
f
j
(q)
K
A,q
.
Getting back to the example discussed before, it
should be easy to see that
w
A,q
(r
2
) =
200a
200a + 0.5a
1.25
b
1
+ a
1.25
(b + c)
1
+ 10
while
w
A,q
(r
3
) =
0.5a
1.25
b
1
200a + 0.5a
1.25
b
1
+ a
1.25
(b + c)
1
+ 10
and the other weights can be calculated analogously.
These weights determine the partition factors of the
amount of species A, available in the state q, among the
rules whichneedobjects Afor performingtheir reactions.
At the end, let us assume that one of the rules compet-
ing for A, say rule r
2
, has the following form: AAB
AC, and let us suppose that, according to the point (3)
expressed above, n objects of type A were allocated to
r
2
and m objects of type B were allocated to r
2
too. The
corresponding reaction unit turns out to be
u
r
2
= min{n/2, m}
and this means that 2u
r
2
objects of type Aand u
r
2
objects
of type B are consumed, while u
r
2
objects of type A and
C are produced.
This globally states that u
r
2
objects of type A and u
r
2
objects of type B are replaced by u
r
2
objects of type C.
But, the important thing to point out here is that rule
r
2
is absolutely different from a rule r

having the form

AB C, and this is due to the fact that the two rules
imply different competition factors, and consequently,
different mass partitions. In fact, in the second case the
reaction unit would have been u
r
= min{n, m}.
In general, if S
r
is the set of substances which are
reactants of the rule r, if we set:
R(Y) = {r|Y S
r
}
and
K
Y,q
=

r R(Y)
f
r
(q)
then the reaction unit u
r
(q), of a rule r in the state q, is
given by
u
r
(q) = min

q(Y)f
j
(q)
K
Y,q
|Y S
r

.
The strategy outlined here suggests a natural repre-
sentationof rules as graphs withtwolevels. The rst level
describes the reaction itself (the stoichiometry, that is the
network of physical connections between species), the
second level expresses the layout of regulation which
tune the relative strengths of rules. The formal repre-
sentation of biological networks is the subject of the
following section.
3. Metabolic P Graphs
A Metabolic P system of level 0 (with only one mem-
brane), shortly a MP system, is given by a structure
M = (T, Q, R, F, q
0
) where T is an alphabet of types
of M; Q are the states of M, functions from T to the
set N of natural numbers; R is the set of rules of M
which are denoted by with , strings over T;
F = {f
r
|r R} is the set of reaction maps of M, with
f
r
: Q R taking values in the set R of real numbers;
and q
0
Q is the initial state of M.
The evolution of M in time is given by a dynamical
function : N Q such that (0) = q
0
and, for any
n N, (n + 1) is calculated by (n) by means of the
MPA.
492 V. Manca, L. Bianco / BioSystems 91 (2008) 489498
Fig. 2. Some examples of type nodes.
Fig. 3. Some examples of metabolic reactions nodes.
Fig. 4. Some examples of reactivity nodes.
We propose to represent the dynamical structure
of metabolic P systems, in a way directly readable in
terms of MPAalgorithm, bygraphs whichextendthe Sto-
ichiometric Network Analysis formalism, SNAfor short,
(Clarke, 1980; Segel and Cohen, 2001) developed in the
context of complex reaction networks. Namely, a MP
graph is a structure G = (T, R, F, E, C), where
T is the set of nodes representing types (we can think
of each t T as a container holding a certain amount
of a peculiar kind of substance). We represent such
kind of nodes as big circles labelled with the type of
objects contained in it, that for the sake of simplicity
is depicted inside the circle (see Fig. 2).
R is the set of nodes representing biochemical reac-
tions between types. We represent each of the nodes
in R as a full bullet and we label it with the name of
the reaction represented by that node (see Fig. 3).
Fis the set of nodes labelled by reaction maps. We rep-
resent such kind of nodes (see Fig. 4) with rectangles.
These nodes are connected with a, possibly empty,
set of circles (types) but they are also connected with
exactly one bullet node (simple lines are put from cir-
cles to squares while arrows are drawn from squares
to bullets).
E is a set nodes presenting input or output gates. It
contains two different kind of nodes: input gates and
output gates. Both of them have the triangular shape
depicted in Fig. 5, where input gates have an arc exit-
Fig. 5. An input gate (left) and an output gate (right).
ing from a triangle vertex, and output gates have an
arc entering in the middle of a triangle edge.
C is a set of edges (arcs and connections) between
nodes. Edges are of two different kinds: plain edges
or dashed edges.
(i) Plain edges connect types to biochemical reactions,
in particular they specify reactants and products of
the reaction. Arcs connecting reactants to reactions
are depicted as lines while arcs connecting reactions
to products appear as arrows (oriented arcs).
(ii) Dashed edges which connect types with square
nodes (reactivitynodes) are depictedas dashedlines,
while dashed edges which connect square nodes
with bullets are depicted as dashed arrows (see
Fig. 6). When specifying the reactivity labels, we
will denote amounts of objects by small letters (or
words) corresponding to the capital ones denoting
species. For example, at each instant, the reactivity
Fr in Fig. 6 is equal to a certain constant k multiplied
by the square of the amount of elements of type Z
present into the system at that instant.
Two components are easily distinguishable in MP
graphs: a stoichiometric component and a regulation
component. The stoichiometric component is the sub-
graph obtained after removing from a MP graph G =
(T, R, F, E, C) the nodes F and the dashed arcs which
connect them to the other nodes. This removed part is
the reaction regulation layout of G.
Fig. 6 represents a rst very basic example of network
described by our formalism. Species X, Y and Z are con-
nected to a reaction node R by means of plain edges.
Fig. 6. A very simple MP graph with three biochemical elements X,
Y, and Z, a reaction node R and an reactivity node Fr whose reactivity
is equal to kz
2
, that is the square of amount of elements of type Z
multiplied by a constant factor k.
V. Manca, L. Bianco / BioSystems 91 (2008) 489498 493
Fig. 7. Examples of stoichiometric components of P metabolic graphs.
As usual in P systems, we can represent the biochemical
reaction R as the following rewriting rule:
XY XZ
in fact, species Xand Y are connected to the reaction Rby
means of a line and according to the formalism they are
reactants, while X and Z are connected to R by an arrow
and this means that they are products of the reaction.
The reaction R specied in this way is a transforma-
tion of species Y into species Z that is catalyzed by the
presence of the species X. Moreover, Fig. 6 contains the
specication of a reactivity relation between Z and R and
the corresponding reactivity map is a quadratic polyno-
mial on type Z. This states that, according to the model
depicted, the production of species Z has a promoting
effect.
In Fig. 7 and in Fig. 8 some examples of stoichiomet-
ric components of MP graphs are shown.
The rst example (Fig. 7, top left) represents the case
of a reversible reaction in which species X 1 is trans-
formed into X 2 by means of the reaction R 1 and the
converse way is performed by the reaction R 2 trans-
forming species X 2 into X 1.
The second example in Fig. 7(top right) involves
the creation of a species X 1 by means of a reac-
tion R 1 that has an input gate as a reactant. Then
element X 1 is subject to two different reactions,
labelled R 2 and R 3, that compete for the usage
Fig. 8. Examples of metabolic P graphs.
494 V. Manca, L. Bianco / BioSystems 91 (2008) 489498
of X 1, and which produce elements X 2 and X 3,
respectively.
The third example in Fig. 7(bottom left) depicts the
simple case of a transformation of species X 1 and X 3
into another two X 2 and X 4.
The last example considered in Fig. 7(bottom right)
represents a well known example of an enzymatic reac-
tion. According to the Michaelis and Menten (1913)
model of enzymatic reactions (Briggs and Haldane,
1925), an enzyme E and a substrate S forma complex ES
by means of a rapid and reversible reaction R 1, then the
complex ES can be subject to two different behaviours:
it can either split back into its components (E and S) by
means of reaction R 2 (stating the reversibility of the
complex formation) otherwise the translation of the sub-
strate into the product P can take place by means of the
reaction R 3 that also releases the enzyme E that gets
ready to start again its work.
All the examples of Fig. 7 deal with the rst level of
a regulated stoichiometric network. In fact, all of them
lack a description of reactivities necessary to regulate the
dynamics of a reaction network. On the contrary, we have
the description of both levels of specication in the two
examples depicted in Fig. 8. The rst example (Fig. 8,
left side) completes the description of an enzymatic reac-
tion (depicted in Fig. 7) by adding reaction maps. In this
simple case, according to the MichaelisMenten formu-
lation already discussed, each of the three rules has a
constant kinetic rate, respectively K
1
, K
1
and K
2
. Note
that, to be consistent with literature and to highlight the
reversibility of reaction R 1 we have renamed R 1 the
reaction labelled R 2 in the model depicted in Fig. 7.
The second example (Fig. 8, right side) depicts the
case of a reversible reaction R 1 that transforms type X 1
into X 2. The production of type X 2 is promoted by X 2
itself, as stated by the reactivity of rule R 1 equal to k
1
x
2
.
The other way round is performed by rule R2 with a reac-
tion map which is a function of two types not directly
involved in the reaction (X 3 and X 4), and in particular,
reaction R 2 is promoted by the element X 3 while it is
inhibited, with a square power, by X 4. Finally, a trans-
formation of X 3 into X 4 proceeds at a constant rate k
3
.
Inthe next section, we are goingtouse all the elements
discussed in the previous sections with the purpose to
simulate the dynamics of a model of the mitotic oscilla-
tions as they occur in amphibian embryos.
4. A Case Study: The Mitotic Oscillator in
Amphibian Embryos
Inthis section, we applyour modellingframeworktoa
case study of mitotic oscillator (Goldbeter, 1991, 2004).
Mitotic oscillations are a mechanismexploited by nature
to regulate the onset of mitosis, that is the process of cell
division aimed at producing two identical daughter cells
from a single parent cell. More precisely, mitotic oscil-
lations concern the uctuation in the activation state of
a protein produced by cdc2 gene in ssion yeasts or by
homologs genes in other eukaryotes. The model here
considered focuses on the simplest form of this mecha-
nism, as it is found in early amphibian embryos. Here, the
progressive accumulation of the cyclin protein leads to
the activation of cdc2 kinase. This activation is achieved
by a bind between cyclin and cdc2 kinase forming a com-
plex known as M-phase promoting factor (or MPF). The
complex triggers mitosis and degrades cyclin as well, the
degradation of cyclin leads to the inactivation of the cdc2
kinase that brings the cell back to the initial conditions in
which a new division cycle can take place. In yeasts and
in somatic cells, the cell cycle is subject to the control
of many checkpoints, but the relaying mechanism based
on the activationinactivation of cdc2 kinase remains the
same (Alberts et al., 1997).
Goldbeter proposed a minimal structure for the
mitotic oscillator in early amphibian embryos in which
the two main entities are cyclin and cdc2 kinase. Accord-
ingtothis model, depictedinFig. 9, the signallingprotein
cyclin is produced at a constant rate v
i
and it triggers the
activation (by means of a dephosphorylation) of cdc2
kinase that passes from the inactive form labelled M
+
to
the active one, M. This modication is reversible and the
other way round is performed by the action of another
kinase (not taken into account in the model) that brings
back M in its inactive form M
+
. Moreover, active cdc2
kinase (M) elicits the activation of a protease X
+
, that
when in the active (phosphorylated) form (X) is able to
Fig. 9. The model provided by Goldbeter (1991).
V. Manca, L. Bianco / BioSystems 91 (2008) 489498 495
degrade the cyclin. This activation, as the previous one,
is reversible as stated by the arrow connecting X to X
+
.
The set of differential equations that are used to model
the dynamics of such a system are the following:
dc
dt
= v
i
v
d
x
c
K
d
+ c
K
d
c
dm
dt
= V
1
1 m
K
1
+ (1 m)
V
2
m
K
2
+ m
dx
dt
= V
3
1 x
K
3
+ (1 x)
V
4
x
K
4
+ x
(1)
where V
1
= (c/K
c
+ c)V
M
1
and V
2
= mV
M
3
. All the
details about the elements involved in this set of dif-
ferential equations can be found in Goldbeters paper,
but we recall their meaning here for the ease of read-
ing. Symbol c denotes concentration of cyclin, m and
x the fraction of active cdc2 kinase and cyclin protease
respectively, thus (1 m) and (1 x) represent respec-
tively the fraction of inactive cdc2 kinase and of inactive
cyclin protease. Parameters v
i
and v
d
are the constant
rate of cyclin synthesis and the maximum rate of cyclin
degradation by protease x reached for x = 1, K
d
and
K
c
are the Michaelis constants for cyclin degradation
and for the activation of the phosphatase acting on M,
while k
d
is the rst-order rate constant of degradation
of cyclin. Moreover, V
i
and K
i
, 1 i 4, represent the
normalized parameters characterizing the kinetics of the
four enzymes involved in the reactions dealing with cdc2
kinase and cyclin phosphatase. More precisely, for each
of the four enzymes (not explicitly represented as entities
of the model) V
i
and K
i
are the effective maximum rate
andMichaelis constant dividedbythe total amount of rel-
evant protein target. Finally, V
M1
denotes the maximum
rate of the enzyme associated to the dephosphorylation
of M
+
, while V
M
3
is the maximum rate of the kinase M
reached for m = 1. The dynamics obtained by a numer-
ical solution of differential Eq. (1), in Fig. 10, shows an
Fig. 10. A numerical solution of the set of differential Eq. (1) imple-
menting the model provided by Goldbeter (1991).
oscillatory behaviour in the activation of the three ele-
ments M, C, X that repeatedly go through a state where
cell enters in a mitotic cycle.
In what follows, we showthree models implementing
the system described by Eq. (1). This highlights the fact
that, in general, there is no unique way to translate a
differential equation system into a set of rules suitable
for the P metabolic algorithm. In particular, in the rst
two models we make two different translations of the
differential Eq. (1), while in the third one we explicitly
introduce four enzymes catalyzing the reactions M
M
+
, M
+
M, X X
+
and X
+
X.
The rst model described here is depicted in Fig. 11.
It contains three cooperative rules, the rst one is r
2
that
models the degradation of the cyclin C by means of the
active phosphatase X, the second one is rule r
4
and it
models the activation of the cdc2 kinase (M
+
) elicited
by cyclin C, while the last one is rule r
6
representing the
activation of the phosphatase X
+
performed by means
of the active cdc2 kinase M. From this representation we
can easily derive the following set of rewriting rules and
reaction maps:
r
1
: C , Fr
1
= k
1
r
2
: XC X , Fr
2
=
k
2
k
3
+ c
r
3
: C , Fr
3
= k
4
r
4
: M
+
C MC , Fr
4
=
k
5
(k
6
+ c)(k
7
+ m
+
)
r
5
: M M
+
, Fr
5
=
k
8
k
9
+ m
r
6
: X
+
M XM , Fr
6
=
k
10
k
11
+ x
+
r
7
: X X
+
, Fr
7
=
k
12
k
13
+ x
(2)
in which all the parameters are taken directly from the
model proposed by Goldbeter
1
.
Another important aspect to highlight here is that we
specify an inertia for each of the species considered in
the model. The inertia is a resistance opposed by each
species against the pressure forces pushing them to react
according to the corresponding rules. This aspect is mod-
elled in our systemby introducing a rule Z Zfor each
one of the species Z{C, X, X
+
, M, M
+
}. We call this
kind of rules inertial rules. These rules (an example of
1
Here, for a easier reading, the notation is slightly different from
that of Goldbeter. The correspondence with Goldbeters model is
the following: k
1
= v
i
, k
2
= v
d
, k
3
= K
d
, k
4
= k
d
, k
5
= V
M
1
, k
6
=
K
c
, k
7
= K
1
, k
8
= V
2
, k
9
= K
2
, k
10
= V
M
3
, k
11
= K
3
, k
12
= V
4
and k
13
= K
4
.
496 V. Manca, L. Bianco / BioSystems 91 (2008) 489498
Fig. 11. The rst model of the mitotic oscillator represented by an MP
graph.
which is depicted in Fig. 12) correspond, in MP graphs,
to loop edges.
The dynamics obtained by the simulation of this rst
model of the mitotic oscillator by using MPAis depicted
in Fig. 13. Hereafter, quantities are expressed in terms
of unspecied population units (conventional moles) and
reactivities provide, for any state, pure numbers speci-
fying the relative strength of rules. What is important
is only the relationship between rule strengths. For this
reason, we could normalize the reactivities, with respect
to a chosen constant k, by multiplying them by a factor
1/k.
Fig. 12. An example of inertial rule associated to species X, the reac-
tivity of the rule is a constant value, but this is not mandatory. In all
examples discussed in this paper reactivities of inertial rules will be
constant values.
Fig. 13. MPA evolution of the model described by Fig. 8. All the
parameters and initial concentrations are derived from Goldbeter
(1991) and are the following: k
1
= 0.025/6.4, k
2
= 0.25, k
3
= 0.02,
k
4
= 0.01, k
5
= 3, k
6
= 0.5, k
7
= 0.005, k
8
= 1.5, k
9
= 0.005, k
10
=
1, k
11
= 0.005, k
12
= 0.5 and k
13
= 0.005. Initial quantities are 0.01
for species C, M and X, while 0.99 for species M
+
and X
+
. Moreover,
reactivities of inertial rules are all constant and xed to 6.4.
If we read in a different way the set differential Eq.
(1) we obtain the second model of the mitotic oscilla-
tor as represented in Fig. 14. In this model, there is no
rule involving more than a single species, in fact, C in
R 4 and M in R 6 were removed as catalyst in the
rules and were introduced as arguments in the corre-
sponding reaction maps. The following is the complete
Fig. 14. The second model of the mitotic oscillator represented by an
MP graph.
V. Manca, L. Bianco / BioSystems 91 (2008) 489498 497
list of rules and reaction maps. The graphical represen-
tation leads directly to the following set of rules and
reaction maps:
r
1
: C , Fr
1
=
k
1
100
r
2
: C , Fr
2
=
k
2
x
100(k
3
+ c)
+
k
4
100
r
3
: M
+
M , Fr
3
=
k
5
c
100(k
6
+ c)(k
7
+ m
+
)
r
4
: M M
+
, Fr
4
=
k
8
100(k
9
+ m)
r
5
: X
+
X , Fr
5
=
k
10
m
100(k
11
+ x
+
)
r
6
: X X
+
, Fr
6
=
k
12
100(k
13
+ x)
(3)
that can be used to simulate the second model of the
mitotic oscillator, producing the dynamics depicted in
Fig. 15.
The last model of the mitotic oscillator here proposed
has a different shape. Now we take into consideration
the set of enzymes E
1
, E
2
, E
3
, and E
4
that catalyze
the reactions involving species M, M
+
, X, and X
+
.
All of these four reactions are cooperative and the
constant rates used in the calculation of the systems
dynamics are the effective maximum rates of the four
enzymes divided by the total amount of protein target.
Fig. 15. MPA evolution of the second model, described by Fig. 14.
All the parameters and initial concentrations are taken directly from
Goldbeter (1991) and are here the following: k
1
= 0.025, k
2
= 0.25,
k
3
= 0.02, k
4
= 0.01, k
5
= 3, k
6
= 0.5, k
7
= 0.005, k
8
= 1.5, k
9
=
0.005, k
10
= 1, k
11
= 0.005, k
12
= 0.5 and k
13
= 0.005, initial quan-
tities are 0.01 for species C, M and X, while 0.99 for species M
+
and
X
+
. Moreover, reactivities of inertial rules are all constant and xed
to 1.
Fig. 16. The third model of the mitotic oscillator represented by an
MP graph.
The graphical representation of the model is depicted in
Fig. 16 while the set of rules and reaction maps are the
following:
r
1
: C , Fr
1
=
k
1
100
r
2
: E
1
M
+
E
1
M , Fr
2
=
k
5
100
c
r
3
: E
2
M E
2
M
+
, Fr
3
=
k
8
100
r
4
: E
3
X
+
E
3
X , Fr
4
=
k
10
100
m
r
5
: E
4
X E
4
X
+
, Fr
5
=
k
12
100
r
6
: C , Fr
6
=
k
2
100
x
(4)
The dynamics of this last model oscillates as well as
in the case of the two previous models and it is repre-
sented in Fig. 17. The important thing to consider here
is that this last model is very simple and it is directly
obtainable by the description of the phenomenon, but the
oscillatory behaviour is reproduced quite well too. This
nal model highlights the capabilities of our formalism
to represent all the information needed by the metabolic
algorithm for calculating the dynamics of a biological
network.
498 V. Manca, L. Bianco / BioSystems 91 (2008) 489498
Fig. 17. MPAevolution of the third model, described byFig. 16. All the
parameters and initial concentrations are taken directly fromGoldbeter
(1991) and are here the following: k
1
= 0.025, k
2
= 0.25, k
5
= 3, k
8
=
1.5, k
10
= 1 and k
12
= 0.5, initial quantities are 0.1 for species C, M
and X, while 0.99 for species M
+
and X
+
and 0.5 for E
1
, E
2
, E
3
and
E
4
. Reactivities of inertial rules of enzymes E
1
, . . . , E
4
are xed to
20 while they are chosen equal to 1 for all other species.
5. Conclusions
In this paper, we continue our investigation regarding
the application of P systems to biological phenomena.
A new version of Metabolic P Algorithm (MPA) is pre-
sentedwhich is strictly related to the graphical formalism
of MP graphs, here introduced for providing natu-
ral descriptions of biochemical systems. Interestingly
enough, MPgraphs can also be seen as particular neuron-
like membrane systems, according to P aun (2002) and
Ciobanu et al. (2006) terminology. The direct application
of MPA to the mitotic oscillator in amphibian embryos
reveals its adequacy in the biological modelling. In fact,
three formulations of this biological network have been
developed here. The rst two are directly obtained from
Goldbeters differential equations representation. The
last one is entirely deduced by translating the biologi-
cal description of the phenomenon in our diagrams. It
is worthwhile observing that in this third case an analo-
gous oscillatory pattern is obtained, but its derivation is
conceptually simpler because directly driven by our for-
malism and avoiding many details on the kinetic aspects
of the reactions.
This work suggested some important questions which
have been addressed in subsequent papers: howis it pos-
sible to compare and evaluate the translations of the same
differential model into different MP graphs? What is the
role of inertial rules and their interpretation in differen-
tial terms? (see Fontana and Manca, 2007). And nally,
another fundamental issue, for a wider application of MP
graphs in the modelling of biological dynamics, is the
denition of general methods for evaluating the values
of parameters occurring in reaction maps (see Manca, in
press).
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