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GRADUATE PROGRAM IN ENGINEERING
RESEARCH TITLE PROPOSAL:
USING A TIMED CONCURRENT CONSTRAINT PROCESS CALCULUS
FOR MODELING BIOMOLECULAR INTERACTIONS
Research in Avispa: Concurrency Theory and Applications
Cali (Colombia), Tuesday January 13th, 2009
______________________________________________________________________
Using a Timed Concurrent Constraint Process Calculus for
Modeling Signal Transduction Systems
(Graduate Research Draft Proposal)
Diana Hermith, BSc. In Molecular Biology
Graduate Student
Program in Engineering Emphasis in Computer Systems
[email protected]
Research in Avispa: Concurrency Theory and ApplicationsPontificia Universidad
Javeriana, Cali
Cali (Colombia), Tuesday January 13th
2009
ABSTRACT
Most biological functions are mediated by protein interactions. These interactions can be
physical, such as when two proteins form a complex, or “logical,” such as when one or more
proteins control the behavior of one or more other proteins without physical interaction.
Metabolic pathways provide us with many examples of these kind of interactions. These
molecules have an extracellular domain, a membrane domain, and an intracellular domain. The
association of the corresponding intracellular domains allows the molecule to transmit the signal
inside the cell.
The number of proteins and other molecules participating in the events
involving signal transduction increases as the process emanates from the initial stimulus,
resulting in a "signal cascade," beginning with a relatively small stimulus that elicits a large
response.
We are planning gain a comprehensive and predictive understanding of the dynamic,
interconnected processes underlying living systems, in these case, the G Protein Signal Cascade,
with a NTCC model that could resolve some biological queries. The first goal would be,
identify and characterize the biomolecular machinery of G Protein Signal Cascade as concurrent
computation, using process algebra: the NTCC calculus.
The second one, develop the
computational capabilities to advanced understanding of complex biological systems and
predict their behavior.
1
GRADUATE PROGRAM IN ENGINEERING
RESEARCH TITLE PROPOSAL:
USING A TIMED CONCURRENT CONSTRAINT PROCESS CALCULUS
FOR MODELING BIOMOLECULAR INTERACTIONS
Research in Avispa: Concurrency Theory and Applications
Cali (Colombia), Tuesday January 13th, 2009
______________________________________________________________________
interactions, one protein affects another
CONTENTS
protein by, for example, regulating its
I. Introduction
2
expression or changing the concentration of
a factor that, in turn, is sensed by the target
II. State of the Art (Short)
4
protein. The two modes of interaction are
not exclusive.
III.
Detailed Description of the G
Protein Signal Cascade
The same proteins can
interact both physically and logically.1
5
Metabolic pathways provide us with many
IV. Why to develop a model by using
examples of logical interactions.
NTCC calculus?
concentration of a product is often “sensed”
8
The
by other proteins in its synthetic cascade
References
14
and modulates their activity. The presence
of hormones is detected by cell surface
receptors and transmitted to other proteins
I. INTRODUCTION
in the cell that can interact with the genetic
Most of biological functions are mediated
material to activate or repress genes. These
by protein interactions. These interactions
logical
can be physical, such as when two proteins
physical
form a complex, or “logical,” such as when
hemoglobin senses the binding of oxygen
one or more proteins control the behavior of
and transmits the information from one of
one or more other proteins without physical
its subunits to the others via physical
interaction.
physical
interaction. Other examples can be found
interactions are stable complexes, in which
in cell surface receptors. These molecules
the functional unit is formed by more than
have an extracellular domain, a membrane
one protein chain, as in the case of the
domain, and an intracellular
glycogen
and
Binding of a ligand to the extracellular
transient associations, in which the protein
domain can cause these molecules to form
Examples
phosphorylase
of
enzyme,
interactions
interactions.
can
coexist
For
with
example,
domain.
chains are stable by themselves but can also
interact to transmit a signal or as a response
to
external
conditions.
In
logical
1
Anna Tramontano. The Ten Most Wanted
Solutions in Protein Bioinformatics. Anna
Tramontano Chapman & Hall/CRC; ISBN:
1584884916; 216pp.; 2005.
2
GRADUATE PROGRAM IN ENGINEERING
RESEARCH TITLE PROPOSAL:
USING A TIMED CONCURRENT CONSTRAINT PROCESS CALCULUS
FOR MODELING BIOMOLECULAR INTERACTIONS
Research in Avispa: Concurrency Theory and Applications
Cali (Colombia), Tuesday January 13th, 2009
______________________________________________________________________
dimers (i.e., to associate with another
the order of milliseconds in the case of ion
receptor chain).
flux, or minutes for the activation of
The association of the
corresponding intracellular domains allows
protein-
and
lipid-mediated
kinase
the molecule to transmit the signal inside
cascades, but some can take hours, and
the cell (Figure 1).
even days (as is the case with gene
expression), to complete. The number of
proteins and other molecules participating
in the events involving signal transduction
increases as the process emanates from the
initial stimulus, resulting in a "signal
cascade," beginning with a relatively small
stimulus that elicits a large response. This
is referred to as amplification of the signal.2
Fig. 1.
The binding of a ligand to the
extracellular domain of a transmembrane
receptor might cause its binding to a
coreceptor (which can be the same or a
different
interaction
protein).
between
The
the
subsequent
intracellular
domains can trigger signaling, for example,
by activating a transcription factor that, in
turn, activates the required genes.
An environmental signal, such as a
hormone, is first received by interaction
with a cellular component, most often a
cell-surface receptor. The information that
the signal has arrived is then converted into
other chemical forms, or transduced. The
signal is often amplified before evoking a
response. Feedback pathways regulate the
entire signaling process.
In biology, signal transduction refers to any
process by which a cell converts one kind
of signal or stimulus into another. Most
processes of signal transduction involve
ordered sequences of biochemical reactions
inside the cell, which are carried out by
Fig 2. Signal Transduction
enzymes, activated by second messengers,
resulting in a signal transduction pathway.
Such processes are usually rapid, lasting on
2
http://en.wikipedia.org/wiki/Signal_transduction
3
GRADUATE PROGRAM IN ENGINEERING
RESEARCH TITLE PROPOSAL:
USING A TIMED CONCURRENT CONSTRAINT PROCESS CALCULUS
FOR MODELING BIOMOLECULAR INTERACTIONS
Research in Avispa: Concurrency Theory and Applications
Cali (Colombia), Tuesday January 13th, 2009
______________________________________________________________________
II. STATE OF THE ART (Short)
Thus, in addition to our curiosity about the
Cell Signaling or Signal Transduction, is
fascinating mechanism that cells use to
the study of the mechanisms that enable the
respond to signals, there is practical
transfer
information.
motivation to better understanding the
Signaling impinges on all aspects of
processes of cellular signaling, in wich
biology, from development to disease.
protein-protein interactions play a central
Many diseases, such as cancer, involve
role.
of
malfunction
pathways.
biological
of
signal
transduction
Mathematical modeling and
The behavior of a signal-transduction
simulation in this field has the porpuse to
system depends on dynamic interactions
help and guide the biologist in designing
among its proteins. The combined effects
experiments and generally to establish a
of these interactions are difficult to predict
conceptual framework in which to think
from intuition alone.
(Kitano et al, 2003).
insufficient, a mathematical model is often
When intuition is
useful for acquiring a quantitative and
G-proteins represent a crucial family of
predictive understanding of a complex
signal transduction molecules that govern a
dynamical
variety
functions.
modeling is being increasingly used to aid
Moreover, GPCRs have traditionally been
in studies of cellular signaling. However,
(and continue to be) a major exploitable
current models are still far from capturing
drug target, giving rise to a plethora of
all of the relevant mechanistic details of
clinically relevant molecules. Thus, a more
signal-transduction systems that must be
complete understanding of the fundamental
considered to provide realistic and complete
properties of GPCRs and how they interact
pictures of how these systems work.
with, and activate, their target G-proteins is
particular, models often fail to account for
of utmost importance to future drug
the
discovery (Johnston et al, 2006).
interactions, such as how these interactions
of
physiological
system,
complexities
and
of
mathematical
In
protein-protein
depend on contextual details at the level of
How GPCRs operate is one of the most
protein sites.
fundamental questions in the field of
that address this problem involve the use of
transmembrane signal transduction.
rules
to
New modeling approaches
represent
protein-protein
4
GRADUATE PROGRAM IN ENGINEERING
RESEARCH TITLE PROPOSAL:
USING A TIMED CONCURRENT CONSTRAINT PROCESS CALCULUS
FOR MODELING BIOMOLECULAR INTERACTIONS
Research in Avispa: Concurrency Theory and Applications
Cali (Colombia), Tuesday January 13th, 2009
______________________________________________________________________
interactions, rules are also useful for
modification is modeled as communication
representing other types of biomolecular
and the subsequent change of channel
interactions.
names. Based on these three principles the
pi calculus allows to fully represent
The introduction of rules greatly eases the
complex molecular structures and signaling
task of specifying a model that incorporates
events (Table 1) (Shapiro et al, 2000).
details at the level of protein sites. A rule—
such as “ligand binds receptor with rate
constant k whenever ligand and receptor
have free binding sites”— describes the
features of reactants that are required for a
particular type of chemical transformation
to
take
place.
Rules
simplify the
specification of a model when the reactivity
of a component in a system is determined
by only a subset of its possible features
(Hlavacek et al, 2006).
Table 1. Pi calculus modeling of typical
Other authors propose that the concurrency
molecular structures involved in Signaling
paradigm and the pi calculus theory are
Transduction Pathways and key signaling
uniquely suited to model and study
events.
biomolecular processes in general and
Signaling
Transduction
pathways
in
III.
DETAILED DESCRIPTION OF
particular. Within the particular framework
THE G PROTEIN SIGNAL CASCADE3
of the pi calculus, they set three principles
Most signal molecules targeted to a cell
for this correspondence; first, as primitive
bind at the cell surface to receptors
process,
functional
embedded in the plasma membrane. Only
signaling domain. Second, they model the
signal molecules able to cross the plasma
they
component
choose
residues
the
of
domains
as
communication channels that construct a
process. Finally, molecular interaction and
3
http://www.rpi.edu/dept/bcbp/molbiochem/MB
Web/mb1/part2/signals.htm#animat1
5
GRADUATE PROGRAM IN ENGINEERING
RESEARCH TITLE PROPOSAL:
USING A TIMED CONCURRENT CONSTRAINT PROCESS CALCULUS
FOR MODELING BIOMOLECULAR INTERACTIONS
Research in Avispa: Concurrency Theory and Applications
Cali (Colombia), Tuesday January 13th, 2009
______________________________________________________________________
membrane (e.g., steroid hormones) interact
include:
altered ligand affinity, receptor
with intracellular receptors. A large family
dimerization or oligomerization, control of
of cell surface receptors have a common
receptor localization, including transfer to
structural motif, 7 transmembrane -
or removal from the plasma membrane,
helices. Rhodopsin was the first of these to
promoting close association with other
have its 7-helix structure confirmed by X-
signal proteins.
ray crystallography.
G-proteins
are
heterotrimeric,
with 3
Rhodopsin is unique. It senses light, via a
subunits , , . A G-protein that activates
bound chromophore, retinal. Most 7-helix
cyclic-AMP formation within a cell is
receptors
the
called a stimulatory G-protein, designated
extracellular side of the plasma membrane
Gs with alpha subunit Gs. Gs is activated,
that recognize and bind signal molecules
e.g., by receptors
(ligands). For example., the -adrenergic
epinephrine
receptor is activated by epinephrine and
adrenergic receptor is the GPCR for
norepinephrine.
epinephrine.
The signal is usually passed from a 7-helix
hormone
signal
have
domains
facing
and
for the
glucagon.
hormones
The
-
receptor to an intracellular G-protein.
outside
Seven-helix receptors are thus called
GPCR, or G-Protein-Coupled Receptors.
GPCR
Approx. 800 different GPCRs are encoded
plasma
membrane

AC
GDP GTP
in the human genome.
GTP
G-protein-Coupled Receptors may dimerize
GDP
cytosol
ATP cAMP + PPi
Fig. 3 The G Protein Signal Cascade4
or form oligomeric complexes within the
membrane. Ligand binding may promote
The  subunit of a G-protein (G) binds
oligomerization, which may in turn affect
GTP, and can hydrolyze it to GDP + Pi.. 
activity of the receptor. Various GPCRinteracting
proteins
receptor function.
(GIPs)
modulate
Effects of GIPs may
4
Molecular tinkering of G protein-coupled
receptors: an evolutionary success”. The
EMBO Journal Vol. 18 No. 7 pp. 1723-1729,
1999.
6
GRADUATE PROGRAM IN ENGINEERING
RESEARCH TITLE PROPOSAL:
USING A TIMED CONCURRENT CONSTRAINT PROCESS CALCULUS
FOR MODELING BIOMOLECULAR INTERACTIONS
Research in Avispa: Concurrency Theory and Applications
Cali (Colombia), Tuesday January 13th, 2009
______________________________________________________________________
and  subunits have covalently attached
Phase 4. Adenylate Cyclase, activated by
lipid anchors that bind a G-protein to the
the
plasma
synthesis of cAMP.
membrane
Adenylate
cytosolic
Cyclase
transmembrane
protein,
(AC)
with
surface.
is
stimulatory
G.-GTP,
catalyzes
a
cytosolic
domains forming the catalytic site.
Phase
5.
Protein
Dependent
Kinase
Protein
Kinase)
A
(cAMP
catalyzes
transfer of phosphate from ATP to serine or
The sequence of events by which a
threonine residues of various cellular
hormone activates cAMP signaling include
proteins, altering their activity.
the following phases:
The turn off of the signal involves these
Phase 1. Initially G has bound GDP, and 
kind of possibilities:
 and  subunits are complexed together.
G, the complex of  and  subunits,
P1. G hydrolyzes GTP to GDP + Pi.
inhibits G.
(GTPase).
The presence of GDP on G
causes it to rebind to the inhibitory bg
Phase 2. Hormone binding, usually to an
complex. Adenylate Cyclase is no longer
extracellular domain of a 7-helix receptor
activated.
(GPCR), causes a conformational change in
the receptor that is transmitted to a G-
P2. Phosphodiesterases catalyze hydrolysis
protein on the cytosolic side of the
of cAMP  AMP.
membrane. The nucleotide-binding site on
G. becomes more accessible to the cytosol,
P3. Receptor desensitization varies with the
where [GTP] > [GDP]. G. releases GDP
hormone.
and binds GTP (GDP-GTP exchange).
receptor is phosphorylated via a G-protein
In some cases the activated
Receptor Kinase.
The phosphorylated
Phase 3. Substitution of GTP for GDP
receptor then may bind to a protein -
causes another conformational change in
arrestin. -Arrestin promotes removal of
G..
G.-GTP dissociates from the
the receptor from the membrane by
inhibitory  complex and can now bind to
clathrin-mediated endocytosis. -Arrestin
and activate Adenylate Cyclase.
may
also
bind
a
cytosolic
7
GRADUATE PROGRAM IN ENGINEERING
RESEARCH TITLE PROPOSAL:
USING A TIMED CONCURRENT CONSTRAINT PROCESS CALCULUS
FOR MODELING BIOMOLECULAR INTERACTIONS
Research in Avispa: Concurrency Theory and Applications
Cali (Colombia), Tuesday January 13th, 2009
______________________________________________________________________
Phosphodiesterase, bringing this enzyme
IV. WHY TO DEVELOP A MODEL BY
close to where cAMP is being produced,
USING NTCC CALCULUS?
contributing to signal turnoff.
Partial information arises naturally in the
description of biological systems.
It is
P4. Protein Phosphatase catalyzes removal
possible to distinguish two main kinds of
by hydrolysis of phosphates that were
partial information when modeling those
attached to proteins via Protein Kinase A.
systems:
While
quantitative
partial
and
behavioral.
quantitative
information
The signal amplification is an important
usually involves incomplete information on
feature of signal cascades. One hormone
the state of the system (e.g., the set of
molecule can lead to formation of many
possible values that a variable can take),
cAMP molecules. Each catalytic subunit of
partial behavioral information refers to the
Protein Kinase A catalyzes phosphorylation
uncertainty associated to behavior
of many proteins during the life-time of the
interactions (e.g., the unknown relative
cAMP.
speeds on which two systems interact).
Different isoforms of G have
For example, the
Finding precise ways of expressing these
when it binds GTP,
kinds of partial information can help to
different signal roles.
stimulatory Gs
activates Adenylate cyclase. An inhibitory
Gi, when it binds GTP, inhibits Adenylate
cyclase.
of
Different effectors and their
better
understand
complex
pattern
behaviors, frequent in biological systems.
Partial information is a central feature of
Concurrent
Constraint
Programming
receptors induce Gi, to exchange GDP for
(CCP), a well-established formalism for
GTP than those that activate Gs.
concurrency.
complex of G 
The
In CCP, processes interact
that is released when G
with each other by telling and asking partial
binds GTP is itself an effector that binds to
information represented as constraints (e.g.,
and activates or inhibits several other
x < 42). Perhaps the most appealing and
proteins.
For example, G
inhibits one
of several isoforms of Adenylate Cyclase,
contributing to rapid signal turnoff in cells
that express that enzyme.
distinctive feature of CCP is that it
combines the traditional operational view of
process calculi with a declarative one based
upon logic. In other words, the process
terms can be viewed at the same time as
8
GRADUATE PROGRAM IN ENGINEERING
RESEARCH TITLE PROPOSAL:
USING A TIMED CONCURRENT CONSTRAINT PROCESS CALCULUS
FOR MODELING BIOMOLECULAR INTERACTIONS
Research in Avispa: Concurrency Theory and Applications
Cali (Colombia), Tuesday January 13th, 2009
______________________________________________________________________
computing agents and logic formulas. This
about the uncertainty in the occurrence time
combination allows CCP to benefit from
of many biological phenomena (Gutierrez
the large body of techniques of both process
et al, 2006).
calculi and logic. For these reasons CCP
can be a convenient framework to describe
Signal-transduction
and reason about biological systems.
viewed as a molecular circuit. We begin by
In
challenges
can
posed
be
this paper we propose works with ntcc, a
examining
timed process calculus based on CCP, as a
transferring extracellular information to a
suitable language for analyzing biological
cell's interior:
systems.
the
pathways
by
In ntcc the above-mentioned
kinds of partial information are naturally
Phase 1. Membrane receptors transfer
captured.
On the one hand, partial
information from the environment to the
quantitative information is captured by the
cell's interior. A few nonpolar signal
notion of constraint system, a structure that
molecules such as estrogens and other
gives
(logic)
steroid hormones are able to diffuse through
constraints.
the cell membranes and, hence, enter the
Since constraint systems are parametric to
cell. Once inside the cell, these molecules
ntcc, by choosing the appropriate constraint
can bind to proteins that interact directly
system(s) several kinds of conditions, at
with DNA and modulate gene transcription.
different levels of detail, can be stated.
Thus, a chemical signal enters the cell and
This could be particularly useful in the
directly alters gene-expression patterns.
coherence
inference
and
capabilities
defines
over
description of quantitative information. For
instance, one could think of a constraint
However, most signal molecules are too
system
equations
large and too polar to pass through the
interacting with others over, say, integers or
membrane, and no appropriate transport
real intervals. On the other hand, partial
systems are present. Thus, the information
behavioral information is represented by
that signal molecules are present must be
non-deterministic
asynchronous
transmitted across the cell membrane
operators available in ntcc. The interplay of
without the molecules themselves entering
these operators in the discrete time of ntcc
the cell. A membrane-associated receptor
over
differential
and
allows to explicitly describe and reason
9
GRADUATE PROGRAM IN ENGINEERING
RESEARCH TITLE PROPOSAL:
USING A TIMED CONCURRENT CONSTRAINT PROCESS CALCULUS
FOR MODELING BIOMOLECULAR INTERACTIONS
Research in Avispa: Concurrency Theory and Applications
Cali (Colombia), Tuesday January 13th, 2009
______________________________________________________________________
protein often performs the function of
cyclic GMP, calcium ion, inositol 1,4,5-
information transfer across the membrane.
trisphosphate, (IP3), and diacylglycerol.
Such a receptor is an intrinsic membrane
The use of second messengers has several
protein that has both extracellular and
consequences. First, second messengers are
intracellular domains. A binding site on the
often free to diffuse to other compartments
extracellular domain specifically recognizes
of the cell, such as the nucleus, where they
the signal molecule (often referred to as the
can influence gene expression and other
ligand). Such binding sites are analogous
processes.
to enzyme active sites except that no
amplified significantly in the generation of
catalysis takes place within them.
The
second messengers. Enzymes or membrane
interaction of the ligand and the receptor
channels are almost always activated in
alters the tertiary or quaternary structure of
second-messenger
the receptor, including the intracellular
activated macromolecule can lead to the
domain. These structural changes are not
generation of many second messengers
sufficient to yield an appropriate response,
within the cell. Thus, a low concentration
because they are restricted to a small
of signal in the environment, even as little
number of receptor molecules in the cell
as a single molecule, can yield a large
membrane. The information embodied by
intracellular signal and response. Third, the
the presence of the ligand, often called the
use of common second messengers in
primary messenger, must be transduced into
multiple signaling pathways creates both
other forms that can alter the biochemistry
opportunities and potential problems. Input
of the cell.
from several signaling pathways, often
called
Phase
2.
information
Second
from
messengers
the
relay
Second, the signal may be
cross
generation;
talk,
concentrations
of
may
each
affect
common
the
second
receptor-ligand
messengers. Cross talk permits more finely
complex. Changes in the concentration of
tuned regulation of cell activity than would
small molecules, called second messengers,
the
constitute the next step in the molecular
pathways.
information circuit. Particularly important
talk can cause second messengers to be
second messengers include cyclic AMP and
misinterpreted.
action
of
individual
independent
However, inappropriate cross
10
GRADUATE PROGRAM IN ENGINEERING
RESEARCH TITLE PROPOSAL:
USING A TIMED CONCURRENT CONSTRAINT PROCESS CALCULUS
FOR MODELING BIOMOLECULAR INTERACTIONS
Research in Avispa: Concurrency Theory and Applications
Cali (Colombia), Tuesday January 13th, 2009
______________________________________________________________________
Phase 3. Protein phosphorylation is a
signaling
common means of information transfer.
terminated
Many second messengers elicit responses
uncontrolled cell growth and the possibility
by activating protein kinases.
of cancer.
These
processes
that
properly
fail
may
to
be
lead
to
enzymes transfer phosphoryl groups from
ATP to specific serine, threonine, and
As we shall see, the use of protein modules
tyrosine residues in proteins.
in various combinations is a clear, even
dominant, theme in the construction of
We previously encountered the cAMP-
signal-transduction
dependent protein kinase.
This protein
transduction proteins have evolved by the
kinase and others are the link that
addition of such ancillary modules to core
transduces changes in the concentrations of
domains to facilitate interactions with other
free second messengers into changes in the
proteins or cell membranes. By controlling
covalent structures of proteins. Although
which proteins interact with one another,
these changes are less transient than the
these modules play important roles in
changes
determining the wiring diagrams for signal-
in
secondary-messenger
concentrations, protein phosphorylation is
not
irreversible.
phosphatases
are
Indeed,
proteins.
Signal-
transduction circuits.
protein
enzymes
that
(Bockaert,
1999)
G
protein
coupled
hydrolytically remove specific phosphoryl
receptors (GPCRs; 7TM receptors; seven
groups from modified proteins.
transmembrane
domain
receptors;
heptahelical receptors; G proteinlinked
Phase 4. The signal is terminated. Protein
receptors [GPLR]) are the largest family of
phosphatases are one mechanism for the
transmembrane
termination of a signaling process. After a
accounting for more than 1% of the protein
signaling process has been initiated and the
coding capacity of the human genome. All
information has been transduced to affect
known
other cellular processes, the signaling
architecture of seven membrane spanning
processes must be terminated.
helices connected by intra and extracellular
such
termination,
cells
Without
lose
GPCRs
receptors
share
in
a
humans,
common
their
loops. The extracellular loops contain two
responsiveness to new signals. Moreover,
highly conserved cysteine residues that
11
GRADUATE PROGRAM IN ENGINEERING
RESEARCH TITLE PROPOSAL:
USING A TIMED CONCURRENT CONSTRAINT PROCESS CALCULUS
FOR MODELING BIOMOLECULAR INTERACTIONS
Research in Avispa: Concurrency Theory and Applications
Cali (Colombia), Tuesday January 13th, 2009
______________________________________________________________________
form disulphide bonds to stabilize the
Signal transduction pathways allow cells to
structure of the receptor. They recognize
respond to environmental signals. In these
diverse messengers such as light, odorants,
pathways, a signal is amplified such that
small
and
each step in the pathway results in a large
Most GPCRs act as
number of activated components than in the
molecules,
neurotransmitters.
guanine
hormones
nucleotide
factors;
exchange
previous step.
This phenomenon, called
activated by ligand binding, they promote
signal amplification, caused the liver cell
GDP
associated
for example, to release a significant number
heterotrimeric guanine nucleotide binding
of glucose molecules after detecting just a
(G) proteins. These in turn activate effector
single
enzymes or ion channels. GPCRs are
Amplification can occur at many points in
involved in a range of physiological roles
the pathway.
which include the visual sense, smell,
epinephrine remains bound to the receptor,
behavioural regulation, functions of the
the receptor can activate a succession of G
autonomic nervous system and regulation
proteins. In addition, each adenylyl cyclase
of the immune system and inflammation.
enzyme can convert numerous ATPs into
GPCRs are divided into 6 classes based on
cyclic AMP molecules.
sequence
enzymes
GTP
exchange
homology
on
and
functional
molecule
in
of
epinephrine.
For example, as long as
the
Other activated
pathway
can
also
similarity; the main mammalian families
continually
are
component that activates just a single
classes
A/1
C/3.
(From
www.reactome.com)
catalyze
reactions.
One
enzyme, however, is the G protein. A G
protein must remain attached to the
Class A/1 (Rhodopsin like)
adenylyl cyclase enzyme in order for the
Class B/2 (Secretin receptor family)
enzyme to remain activated.
Class C/3 (Metabotropic
glutamate/pheromones)
Termination of the cellular response is an
Class D/4 (fungal mating pheromone
important as its initiation. In order for a
receptors)
cell to respond only when a signal is
Class E/5 (cAMP receptors)
present, the many players in the pathway
Class F/6 (Frizzled/Smoothened)
have to regulated so that they are activate
for only a short period of time.
12
GRADUATE PROGRAM IN ENGINEERING
RESEARCH TITLE PROPOSAL:
USING A TIMED CONCURRENT CONSTRAINT PROCESS CALCULUS
FOR MODELING BIOMOLECULAR INTERACTIONS
Research in Avispa: Concurrency Theory and Applications
Cali (Colombia), Tuesday January 13th, 2009
______________________________________________________________________
We are planning, gain a comprehensive and
understanding
of
complex
biological
predictive understanding of the dynamic,
systems and predict their behavior.
interconnected processes underlying living
systems, in these case, the G Protein Signal
Previous
Cascade. For these purpose, is necessary to
concurrent computational processes, each
have
biological entity is a process that may carry
information
about
dynamics,
abstractions
state
interacts
that
with
in
molecular structure and biochemical detail
some
of each interaction, to explore and apply
processes.
formal semantics to simulate, analyze and
process algebras, such as the pi calculus can
compare the biomolecular G Protein Signal
be
Cascade System. So in these first draft, we
reasoning about this kind of systems.
applied
and
shows,
other
Prior proposals5 based on
for
make
an
appropiate
not yet include, the computational model,
but we now, that the molecules involves in
The benefits of the NTCC approach should
the
be an unified view of the system, the
signal
capability,
pathways
have
interaction
reactions/interactions
and
simulation and analysis and a comparative
modification, with the same principles came
power and scalability to enrich the model
from
chemistry,
with experimental (quantitative) data. The
enzymatic reactions, metabolic pathways,
idea in this sense, is to explore and combine
signal-transduction pathways and ultimately
the metodology with implementations than
the entire cell.
Biology is driven by
permit an interplay between collecting data
quantities (e.g., energy, time, affinity,
in experiments (experimental biology) and
distance, amount of components) so we
the NTCC model, with the aim to capture
would need to consider this.
some mechanistic understanding of how the
chemistry,
organic
systems under study works, by validating
The goal 1 would be, identify and
the model under various conditions that
characterize the biomolecular machinary of
correspond to the experiments and by
G Protein Signal Cascade as concurrent
comparing
computation, using Process algebra: the
experimental
NTCC calculus. The second one, develop
discrepancies
the computational capabilities to advance
the
outcomes
data,
one
between
to
can
the
identify
hypothetical
5
Regev et al. 2001.
http://www.wisdom.weizmann.ac.il/~udi/papers
/pi_calculus.pdf
13
GRADUATE PROGRAM IN ENGINEERING
RESEARCH TITLE PROPOSAL:
USING A TIMED CONCURRENT CONSTRAINT PROCESS CALCULUS
FOR MODELING BIOMOLECULAR INTERACTIONS
Research in Avispa: Concurrency Theory and Applications
Cali (Colombia), Tuesday January 13th, 2009
______________________________________________________________________
mechanisms
and
experimental
role of -arrestin?. How we can describe
observations.
These differences can be
the activation of cAMP-Dependent Protein
used to suggest new hypotheses, which
Kinase (Protein Kinase A)?. What causes
serve to adjust the model and need to be
the enzyme to be inhibited in the absence of
validated
cyclic AMP?. How is activation by cyclic
the
experimentally,
or
new
experiments, which can confirm or falsify
AMP turned off?.
What reaction is
the modeling hypotheses.
catalyzed
enzyme
The goal will be find an appropriate model
Phosphatase?.
by
the
Protein
for G Protein Signal Cascade that include
molecular structure, behavior and biological
REFERENCES
formal semantics.
xpected results we are thinking to obtain: a
unified view of structure and dynamics of G
Protein
Signal
molecular
Cascade,
information
a
detailed
(complexes,
molecules, domains, residues) in visible
form,
a
complex
dynamic
behavior
[1] Executable Cell Biology. Jasmin Fisher
and Thomas A Henzinger. Nature
Biotechnology, volume 25 number 11
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[2] Representing Biomolecular Processes
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and Ehud Shapiro. American Association
for Artificial Intelligence (www.aaai.org).
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modular system.
We want construct a NTCC model that
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Wanted
Solutions
in
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Anna
Tramontano
Chapman
&
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ISBN:
1584884916; 216pp.; 2005.
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Cyclase. How is the signal turned off at
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http://www.wisdom.weizmann.ac.il/~udi/pa
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Constraint
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Arbelaez,
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each step?. How we can be simulate the
14
GRADUATE PROGRAM IN ENGINEERING
RESEARCH TITLE PROPOSAL:
USING A TIMED CONCURRENT CONSTRAINT PROCESS CALCULUS
FOR MODELING BIOMOLECULAR INTERACTIONS
Research in Avispa: Concurrency Theory and Applications
Cali (Colombia), Tuesday January 13th, 2009
______________________________________________________________________
[6]
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Concurrent
Constraint
Programming for Analysing Biological
Systems. J. Gutierrez, J. Perez, C. Rueda
and
F.
Valencia.
http://www.elsevier.nl/locate/entcs
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usando Cálculos de Procesos Concurrentes.
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Cali (Colombia), diciembre de 2005.
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[13] Rules for Modeling SignalTransduction Systems. W. Hlavacek, J.
Faeder, M. Blinov, R. Posner, M. Hucka,
W. Fontana. Sciences STKE, 2006.
[14] The Complexity of Complexes in
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S.
Perelson,Byron
Goldstein.
Biotechnology and Bioengineering, Vol.
84, No. 7, December 30, 2003, 783-794 pp.
[15] Formal Methods for Biochemical
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Gilmore, Jane Hillston and Vladislav
Vyshemirsky.
http://homepages.inf.ed.ac.uk/jeh/papers.ht
ml
[9] Systems Biology: Looking at
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15