UCI ICS IGB SISL The Sigmoid Biological Pathway Modeling System Eric Mjolsness [email protected]...
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Transcript of UCI ICS IGB SISL The Sigmoid Biological Pathway Modeling System Eric Mjolsness [email protected]...
UCI ICS IGB SISL
The Sigmoid Biological Pathway Modeling System
Eric [email protected]
Scientific Inference Systems Laboratory
Institute for Genomics and Bioinformatics, and
Department of Computer Science
University of California, Irvine USA
http://www.ics.uci.edu/~emj
Based on joint work with Pierre Baldi, Lee Bardwell, Jianlin Cheng, Ben Compani, Andre Levchenko, Lucas Scharenbroich, Trent Su
UCI ICS IGB SISL
Rationale
• Mathematics is still the language of nature– Even in biology, after physical science
• Smooth the process of biology to mathematics to computation and back
UCI ICS IGB SISL
E.g. MAP Kinase Cascade
K3⇒K4K3
*
K2⇒K3
*
K2*⇒K3
*
K2**
K1 ⇒K2
**
K1* ⇒K2
**
K1**
With A. Levchenko, B. Shapiro, B. Wold
J. Ferrell model w/o scaffold
UCI ICS IGB SISL
CLV3CLV1
?
Fletcher et al., Science v. 283, 1999
Brand et. al., Science 289, 617-619, (2000)
WUS
UCI ICS IGB SISL
Software architectures for systems biology: Sigmoid & Cellerator
www.sigmoid.org + sourceforgeCheng et al., IEEE Intelligent Systems, May/June 2005
UCI ICS IGB SISL
Autogeneration Architecture
• Schema (UML) to database (SQL, Java)– Reactions, reactants, models, knowledge sources
• Compound reactions to elementary ones• Reactions to dynamical systems
– ODE systems
– Stochastic model sims
• Equilibrium models to dynamical systems
UCI ICS IGB SISL
Specialized Cellerator ArrowsCellerator Form Differential Equation Terms {{A1,A2,...,An}aB,hill[options]} d[B]dt=r+vi[Ai]i=1n∑( )nKn+vi[Ai]i=1n∑( )n {{A1,A2,...,AN}aB,GRN[options]} d[B]dt=r1+exp{−(h+Ti[Ai]nii=1N∑)} {{A1,A2,...,AN}aB,GRN[...,Sigmoid→f]} d[B]dt=rf(h+TgAn) {{A1,A2,...,AN}aB, SSystem[options]}
d[B]dt=1τk+[Ai]Ci+i=1n∏−k−[Ai]Ciii=1n∏⎛⎝⎜ ⎞⎠⎟ {S1,S2,...}⇒{P1,P2,...{{A1,A2,...},{I1,I2,...}}E} d[Pi]dt=kcat[E]1+aq()nq∏sqq∏(1+sq)n−1q∏+L(csq)q∏(1+csq)n−1q∏(1+iq)nq∏1+aq()nq∏(1+sq)nq∏+L(1+csq)nq∏(1+iq)nq∏
Cellerator: Shapiro et al., Bioinformatics 19(5):677-678, 2003www.cellerator.info
UCI ICS IGB SISL
SIGMOID Model Explorer (SME)
JGraph
SigmoidPathway DatabasePostgreSQL
Cellerator/kMechSimulation
EngineMathematicaTM
The Internet
Future Expansion:Parameter Optimization,Data Mining, …
DatabaseSchema
UML
SIGMOID Architecture:A Service-Oriented Distributed Computing System for Systems Biology
SBML
AX
gen
Da
tab
as
e
Ac
ce
ss
Mo
de
l T
ran
sla
tio
n
MiddlewareWeb Services (SOAP)
...
Biologists
Bioinformaticians
OJ
B
JL
ink
UCI ICS IGB SISL
Filtered List of Appropriate Biological Reaction Assignments Appears in the Left Panel
UCI ICS IGB SISL
MAPK/Scaffold Modeling
MAPKKK (K3)
MAPKK (K2)
MAPK (K1)
Input(s)
Output
Shapiro et al., 1st Int. Conf. Systems Biology, 2000; in Foundations of Systems Biology, MIT Press 2001
UCI ICS IGB SISLReactions in ScaffoldedMAP Kinase Cascade
• Phosphorylation in Solution
• Binding to Scaffold
• Phosphorylation in Scaffold
Kij ⇔
Phi
Ki+1ai+1
K ij+1 i =1,K ,n−1, j =0,K ,aj −1
⎧⎨⎩⎪
⎫⎬⎭⎪
Sp1 ,L , pi =ε,L ,pn
+ K ij ↔ Sp1 ,L ,pi =j ,L ,pn{ } , pi =
ε,0,1,K ,ai , i ≠ j0,1,K ,ai , i = j
⎧⎨⎩
Sp1 ,L , pi−1=j<ai−1, pi =ai ,L ,pn+ K ⇔ Sp1 ,L ,pi−1=j+1, pi =ai ,L ,pn{ }
Sp1 ,L ,pi−1=j<ai−1, pi =ai ,L ,pn→ Sp1 ,L ,pi−1=j+1, pi =ai ,L ,pn{ }
Shapiro et al., 1st Int. Conf. Systems Biology, 2000; in Foundations of Systems Biology, MIT Press 2001
UCI ICS IGB SISL
NFB Oscillations in Cellerator
Hoffmann, Levchenko, Scott, Baltimore. Science 298:1241, 2003A. Levchenko, Cellerator notebook.
UCI ICS IGB SISL
Amino Acid Syntheses
Asp
Thr
KB
Pyr
Leu
Val
Ile
GlycolysisGlucose TCA cycleAla
+
tRNA-Leu
tRNA-Val
tRNA-Ile
tRNA-Ala
tRNA-ThrLys Met
Kmech: Yang, et al. Bioinformatics 21: 774-780, 2005
UCI ICS IGB SISLBiosynthesis of Valine, Leucine
and Isoleucine
Yang et al., Journal of Biological Chemistry, 280(12):11224-32, Mar 25 2005
UCI ICS IGB SISL
∏∏∏ ∏
+++++
+++++=
−−
q
nq
nq
q
nq
nq
q q
nqq
nq
nqq
nq
f icsLas
icscsLass
Y])1()1[(])1()1[(
])1)(()1[(])1()1[( 11
A GeneralizedMWC Modelfor multiple substrates, inhibitors and activators
T R
L Substrate 1
Inhibitor 1
Activator
. ... .. . . ... ..... .. ...
Substrate 2
.. .. ... .. ... .... .... .
Inhibitor 2
GMWC model: Yang et al: to appear, CSB conference 2005MWC: Cf. Changeux and Edelstein, Science 3 June 2005; 308: 1424-142
UCI ICS IGB SISL
CLV3/WUS networks
V. Agrawal, B. Shapiro, Caltech
Z
wusclv1
clv3Xdiffusive
YL1diffusive
Jönsson et al., Bioinformatics 21(Suppl. 1):i232-i240 June 2005 (ISMB, 4:35pm Sunday)
UCI ICS IGB SISL
Forthcoming Sigmoid Features• new reaction types
– e.g. for CLV3, calcineurin, p53 models
• model search web page• fixed point/Jacobian/critical point algebra• phase plot options• stochastic simulation• param fitting• p:p interaction database• * federate with other databases
UCI ICS IGB SISL
Autogeneration Architecture
• Schema (UML) to database (SQL, Java)– Reactions, reactants, models, knowledge sources
• Compound reactions to elementary ones• Reactions to dynamical systems
– ODE systems
– Stochastic model sims
• Equilibrium models to dynamical systems
UCI ICS IGB SISL
For more information …• Papers
– Sigmoid: Cheng et al., IEEE Intelligent Systems, May/June 2005– Kmech: Yang, et al. Bioinformatics 21: 774-780, 2005
– Cellerator: Shapiro et al., Bioinformatics 19(5):677-678, 2003
– Amino acid synthesis: Yang et al., Journal of Biological Chemistry, 280(12):11224-32, Mar 25 2005
– Plant Gene Regulatory Nets: Jönsson et al., Bioinformatics 21(Suppl. 1):i232-i240 June 2005
– MAPK Scaffold: Shapiro et al., in Foundations of Systems Biology, MIT Press 2001
• URLs– www.sigmoid.org– www.ics.uci.edu/~emj– www.cellerator.info– www.igb.uci.edu/servers/sb.html
• Sigmoid Sponsor: NIGH BISTI (GM069013)