A Systems Biology Approach to Cancer Therapy and Early Detection A Systems Biology Approach to Cancer Therapy and Early Detection

1
A Systems Biology Approach to Cancer Therapy and
Early DetectionA Systems Biology Approach
to Cancer Therapy and Early Detection

• Avijit Ghosh
• Dhruv Pant, Rui Zou, Dave Miller
• Yihua Wang, Hanbing Lin
• Travis Hoppe, Aparna Kumar

Department of Physics Drexel University
2
Outline

• Signal Transduction
• Overview
• Mutations, Oncogenes, Proto-Oncogenes
• Mathematical Models
• Enzymes
• Mutations
• Predicting Putative Oncogenes using Systems
  Biology
• D. Pant A. Ghosh (2005) Biophys. Chem 113(3)
  275-288
• The Results
• Experimentally Validated Results
• New Predictions
• Drugs!
• Spatio-Temporal Modeling
• CellSim
• Overview

3
Signal Transduction

• Controls behavior of cells
• Ion Channels
• Metabolic Pathways
• Cytoskeletal Proteins
• Gene Regulatory Proteins
• Cell cycle
• Cytoskeletal rearrangement

D. Slish Mechanism of Tyrosine Kinase Receptors
U.Platt.
4
The Normal Functioning MAPK Signal Cascade
5
Signaling and Cell Growth

• Input
• EGF Epidermal Growth Factor
• Output
• Signal for gene transcription ERK
• Activation
• Phosphorylation
• GTP/GDP binding

6
EGF stimulation and ERK response
7
Oncogenes and Tumor Suppressor Genes

• Oncogene - A gene (protein) that when mutated or
  inappropriately expressed contributes to cancer
  formation
• Mutations in signal transduction genes
• Mutations in Tumor Suppressor genes
• INHERITED
• Activation
• Point Mutation
• Chromosomal rearrangement
• Gene amplification
• Viral Insertion

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The Ras Protein

• Ras Protein
• Active GTP Bound
• Inactive GDP Bound
• GAP (GTPase Activating Protein)
• Hydrolyzes GTP in Ras
• Gly12 Stops Ras Gap Interactions
• Gln61 Stops hydrolysis

Scheffzick et.al. (1997) Science 277 pp 333-338
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Interactions
10
EGF / MAPK / PLC / PLC-?/ PKC / Calcium / PLA2
Pathways
Ca CaTransp Ca ltgt CaTransp-2Ca 1e-08
144 IP3R IP3 IP3 IP3 ltgt IP3R
1e-20 1 Ca-sequester Ca-sequester
capacitive_Ca_entry ltgt inact_cap_entry
1.2e-11 1 EGFR EGF ltgt L.EGFR
7e-06 0.25 SHC -gt SHC 0.0016667
L.EGFR ltgt Internal_L.EGFR 0.002
0.00033 mGluR Glu ltgt Rec-Glu 2.8e-05
10 G-GDP -gt GGTP BetaGamma 0.0001
GGDP BetaGamma -gt G-GDP 1e-05
GGTP -gt GGDP 0.0133 G-GDP Rec-Glu
ltgt Rec-Glu-Gq 1e-08 0.0001 Glu
Rec-Gq ltgt Rec-Glu-Gq 2.8e-05 0.1
Rec-Glu-Gq -gt GGTP BetaGamma Rec-Glu
0.01 G-GDP mGluR ltgt Rec-Gq 1e-06
1 Rec-Gq mGluRAntag ltgt Blocked-rec-Gq
0.0001 0.01 craf-1 GTP-Ras ltgt
Raf-GTP-Ras 4e-05 0.5 PKC-cytosolic
Ca ltgt PKC-Ca 1e-06 0.5 DAG
PKC-Ca ltgt PKC-Ca-DAG 1.3333e-08 8.6348
PKC-Ca ltgt PKC-Ca-memb 1.2705 3.5026
PKC-Ca-DAG ltgt PKC-DAG-memb 1 0.1
PKC-Ca AA ltgt PKC-Ca-AA 2e-09 0.1
PKC-DAG-AA ltgt PKC-DAG-AA 2 0.2
PKC-cytosolic ltgt PKC-basal 1 50 AA
PKC-cytosolic ltgt PKC-AA 2e-10 0.1
PKC-cytosolic DAG ltgt PKC-DAG 1e-09
0.1 PKC-DAG AA ltgt PKC-DAG-AA 3e-08
2 PLA2-cytosolic Ca ltgt PLA2-Ca
1.6667e-06 0.1 temp-PIP2 PLA2-cytosolic
ltgt PIP2-PLA2 2e-09 0.5 temp-PIP2
PLA2-Ca ltgt PIP2-Ca-PLA2 2e-08 0.1
DAG PLA2-Ca ltgt DAG-Ca-PLA2 5e-09
4 AA -gt APC 0.4 PLA2 Ca
ltgt PLA2-Ca 1e-05 0.1 PLA2 -gt
PLA2-cytosolic 0.17 Ca PLC ltgt
PLC-Ca 5e-06 1 IP3 -gt Inositol
2.5 DAG -gt PC 0.15 GGTP
PLC-Ca ltgt PLC-Ca-Gq 4.2e-05 1
PLC-Ca-Gq -gt GGDP PLC-Ca 0.0133
PLC GGTP ltgt PLC-Gq 4.2e-06 1 Ca
PLC-Gq ltgt PLC-Ca-Gq 5e-05 1
PLC_g Ca ltgt Ca.PLC_g 0.0003 10
Ca PLC_G ltgt Ca.PLC_g 2e-05 10
Ca.PLC_g -gt Ca.PLC_g 0.05 BetaGamma
inact-GEF ltgt GEF-Gprot-bg 1e-05 1
GEF -gt inact-GEF 1 GTP-Ras -gt
GDP-Ras 0.0001 GAP -gt GAP 0.1
inact-GEF CaM-Ca4 ltgt CaM-GEF 0.0001
1 inact-GEF -gt inact-GEF 1
Sos.Grb2 SHC ltgt Shc.Sos.Grb2 8.333e-07
0.1 Sos Grb2 ltgt Sos.Grb2
4.1667e-08 0.0168 Sos -gt Sos
0.001 Grb2 Sos ltgt Sos.Grb2
4.1667e-08 0.0168
locations the volume is a optional
parameter our volume units are Llocation
extracellular 1E-10 Ca-extlocation cytosol
1E-12location endosome 1.6E-13 Ca-sequester
Channelschannel capacitive_Ca_entry Ca-ext -gt
Ca 0.005channel Ca-leak-from-extracell Ca-ext
-gt Ca 0.004channel Ca-leak-to-cytoplasm
Ca-sequester-gtCa 8channel IP3R Ca-sequester
-gt Ca 19.2 conservationReactionsconserve
CaEPump Ca_CaEPumpconserve CaTransp-2Ca
CaTranspconserve mGluR Rec-Glu Rec-Glu-Gq
Rec-Gq Blocked-rec-Gqconserve PLC match
/PLC-/conserve PLA2-cytosolic match
/PLA2/ sum upsum PKC-active PKC-DAG-AA
PKC-Ca-memb PKC-Ca-AA PKC-DAG-memb
sumReactions (native units are
/compartment)Ca CaEPump ltgt Ca_CaEPump
0.003 288Ca_CaEPump -gt CaEPump Ca-ext 72
Ca.PLC_g L.EGFR ltgt Ca.PLC_g_L.EGFR 5e-06
0.8Ca.PLC_g_L.EGFR -gt L.EGFR Ca.PLC_g
0.2 SHC L.EGFR ltgt SHC_L.EGFR 2e-06
0.8SHC_L.EGFR -gt L.EGFR SHC 0.2 MAPK
MAPKK ltgt MAPK_MAPKK 2.7e-05 0.6MAPK_MAPKK
-gt MAPKK MAPK-tyr 0.15 MAPK-tyr MAPKK
ltgt MAPK-tyr_MAPKK 2.7e-05 0.6MAPK-tyr_MAPKK
-gt MAPKK MAPK 0.15 MAPKK Raf-GTP-Ras
ltgt MAPKK_Raf-GTP-Ras 5.5e-06
0.42MAPKK_Raf-GTP-Ras -gt Raf-GTP-Ras
MAPKK-ser 0.105 MAPKK-ser Raf-GTP-Ras ltgt
MAPKK-ser_Raf-GTP-Ras 5.5e-06
0.42MAPKK-ser_Raf-GTP-Ras -gt Raf-GTP-Ras
MAPKK 0.105 craf-1 PKC-active ltgt
craf-1_PKC-active 5e-07 16craf-1_PKC-active
-gt PKC-active craf-1 4 GAP PKC-active
ltgt GAP_PKC-active 1e-05 16GAP_PKC-active -gt
PKC-active GAP 4 inact-GEF PKC-active
ltgt inact-GEF_PKC-active 1e-05
16inact-GEF_PKC-active -gt PKC-active GEF
4 craf-1 PKC-DAG-AA ltgt craf-1_PKC-DAG-AA
5e-07 16craf-1_PKC-DAG-AA -gt PKC-DAG-AA
craf-1 4 GAP PKC-DAG-AA ltgt
GAP_PKC-DAG-AA 1e-05 16GAP_PKC-DAG-AA -gt
PKC-DAG-AA GAP 4 inact-GEF PKC-DAG-AA
ltgt inact-GEF_PKC-DAG-AA 1e-05
16inact-GEF_PKC-DAG-AA -gt PKC-DAG-AA GEF
4 craf-1 PKC-Ca-memb ltgt craf-1_PKC-Ca-memb
5e-07 16craf-1_PKC-Ca-memb -gt
PKC-Ca-memb craf-1 4 GAP PKC-Ca-memb
ltgt GAP_PKC-Ca-memb 1e-05 16GAP_PKC-Ca-memb
-gt PKC-Ca-memb GAP 4 inact-GEF
PKC-Ca-memb ltgt inact-GEF_PKC-Ca-memb 1e-05
16inact-GEF_PKC-Ca-memb -gt PKC-Ca-memb GEF
4 craf-1 PKC-Ca-AA ltgt craf-1_PKC-Ca-AA
5e-07 16craf-1_PKC-Ca-AA -gt PKC-Ca-AA
craf-1 4 GAP PKC-Ca-AA ltgt
GAP_PKC-Ca-AA 1e-05 16GAP_PKC-Ca-AA -gt
PKC-Ca-AA GAP 4 inact-GEF PKC-Ca-AA ltgt
inact-GEF_PKC-Ca-AA 1e-05 16inact-GEF_PKC-Ca-
AA -gt PKC-Ca-AA GEF 4 craf-1
PKC-DAG-memb ltgt craf-1_PKC-DAG-memb 5e-07 16
craf-1_PKC-DAG-memb -gt PKC-DAG-memb craf-1
4 GAP PKC-DAG-memb ltgt GAP_PKC-DAG-memb
1e-05 16GAP_PKC-DAG-memb -gt PKC-DAG-memb
GAP 4 inact-GEF PKC-DAG-memb ltgt
inact-GEF_PKC-DAG-memb 1e-05
16inact-GEF_PKC-DAG-memb -gt PKC-DAG-memb
GEF 4 craf-1 PKC-basal ltgt
craf-1_PKC-basal 5e-07 16craf-1_PKC-basal
-gt PKC-basal craf-1 4 GAP PKC-basal
ltgt GAP_PKC-basal 1e-05 16GAP_PKC-basal -gt
PKC-basal GAP 4 inact-GEF PKC-basal ltgt
inact-GEF_PKC-basal 1e-05 16inact-GEF_PKC-bas
al -gt PKC-basal GEF 4 craf-1 PKC-AA
ltgt craf-1_PKC-AA 5e-07 16craf-1_PKC-AA -gt
PKC-AA craf-1 4 GAP PKC-AA ltgt
GAP_PKC-AA 1e-05 16GAP_PKC-AA -gt PKC-AA
GAP 4 inact-GEF PKC-AA ltgt
inact-GEF_PKC-AA 1e-05 16inact-GEF_PKC-AA
-gt PKC-AA GEF 4 end expandAPC
PLA2-Ca ltgt APC_PLA2-Ca 2.25e-06
21.6APC_PLA2-Ca -gt PLA2-Ca AA 5.4 APC
PIP2-PLA2 ltgt APC_PIP2-PLA2 4.6e-06
44.16APC_PIP2-PLA2 -gt PIP2-PLA2 AA
11.04 APC PIP2-Ca-PLA2 ltgt APC_PIP2-Ca-PLA2
1.5e-05 144APC_PIP2-Ca-PLA2 -gt
PIP2-Ca-PLA2 AA 36 APC DAG-Ca-PLA2 ltgt
APC_DAG-Ca-PLA2 2.5e-05 240APC_DAG-Ca-PLA2
-gt DAG-Ca-PLA2 AA 60 APC PLA2-Ca ltgt
APC_PLA2-Ca 5e-05 480APC_PLA2-Ca -gt
PLA2-Ca AA 120 PLA2-cytosolic MAPK ltgt
PLA2-cytosolic_MAPK 6.5e-06
80PLA2-cytosolic_MAPK -gt MAPK PLA2 20
craf-1 MAPK ltgt craf-1_MAPK 3.25e-06
40craf-1_MAPK -gt MAPK craf-1 10 Sos
MAPK ltgt Sos_MAPK 3.25e-05 40Sos_MAPK -gt
MAPK Sos 10 MAPK-tyr MKP-1 ltgt
MAPK-tyr_MKP-1 0.000125 4MAPK-tyr_MKP-1 -gt
MKP-1 MAPK 1 MAPK MKP-1 ltgt MAPK_MKP-1
0.000125 4MAPK_MKP-1 -gt MKP-1 MAPK-tyr
1 craf-1 PPhosphatase2A ltgt
craf-1_PPhosphatase2A 3.3e-06
25craf-1_PPhosphatase2A -gt PPhosphatase2A
craf-1 6 MAPKK PPhosphatase2A ltgt
MAPKK_PPhosphatase2A 3.3e-06
25MAPKK_PPhosphatase2A -gt PPhosphatase2A
MAPKK-ser 6 MAPKK-ser PPhosphatase2A ltgt
MAPKK-ser_PPhosphatase2A 3.3e-06
25MAPKK-ser_PPhosphatase2A -gt PPhosphatase2A
MAPKK 6 craf-1 PPhosphatase2A ltgt
craf-1_PPhosphatase2A 3.3e-06
25craf-1_PPhosphatase2A -gt PPhosphatase2A
craf-1 6 inact-GEF PKA-active ltgt
inact-GEF_PKA-active 1e-05 36inact-GEF_PKA-act
ive -gt PKA-active inact-GEF 9 GDP-Ras
Shc.Sos.Grb2 ltgt GDP-Ras_Shc.Sos.Grb2 3.3e-07
0.08GDP-Ras_Shc.Sos.Grb2 -gt Shc.Sos.Grb2
GTP-Ras 0.02 PIP2 PLC-Ca ltgt PIP2_PLC-Ca
4.2e-06 40 PIP2_PLC-Ca -gt PLC-Ca DAG
IP3 10 PIP2 PLC-Ca-Gq ltgt PIP2_PLC-Ca-Gq
8e-05 192PIP2_PLC-Ca-Gq -gt PLC-Ca-Gq DAG
IP3 48 PIP2 Ca.PLC_g ltgt PIP2_Ca.PLC_g
1.2e-06 56PIP2_Ca.PLC_g -gt Ca.PLC_g DAG
IP3 14 PIP2 Ca.PLC_g ltgt PIP2_Ca.PLC_g
2.4e-05 228PIP2_Ca.PLC_g -gt Ca.PLC_g DAG
IP3 57 GDP-Ras GEF-Gprot-bg ltgt
GDP-Ras_GEF-Gprot-bg 3.3e-07
0.08GDP-Ras_GEF-Gprot-bg -gt GEF-Gprot-bg
GTP-Ras 0.02 GDP-Ras GEF ltgt GDP-Ras_GEF
3.3e-07 0.08GDP-Ras_GEF -gt GEF GTP-Ras
0.02 GTP-Ras GAP ltgt GTP-Ras_GAP 0.001666
1000GTP-Ras_GAP -gt GAP GDP-Ras 10
GDP-Ras CaM-GEF ltgt GDP-Ras_CaM-GEF 3.3e-07
0.08GDP-Ras_CaM-GEF -gt CaM-GEF GTP-Ras
0.02 CaTransp-2Ca -gt CaTransp Ca-sequester
Ca-sequester 25
11
Leads to..
dcapacitive_ca_entry/dt 1inact_cap_entry -
1.2e-11ca-sequesterca-sequestercapacitive_ca_
entrydca/dt 288ca_caepump
144catransp-2ca 144catransp-2ca
0.5pkc-ca 0.1pla2-ca 0.1pla2-ca
1plc-ca 1plc-ca-gq 10ca.plc_g
10ca.plc_g - 0.003cacaepump -
1e-08cacatranspca - 1e-08cacatranspca
- 1e-06pkc-cytosolicca - 1.6667e-06pla2-cytos
olicca - 1e-05pla2ca - 5e-06caplc -
5e-05caplc-gq - 0.0003plc_gca -
2e-05caplc_g 0.005 capacitive_ca_entry
( ca-ext - ca ) 0.004
ca-leak-from-extracell ( ca-ext - ca )
8 ca-leak-to-cytoplasm ( ca-sequester -
ca ) 19.2 ip3r ( ca-sequester -
ca ) dca-leak-from-extracell/dt
dca-leak-to-cytoplasm/dt dip3r/dt
1e-20ip3rip3ip3ip3 - 1ip3rdcaepump/d
t 288ca_caepump 72ca_caepump -
0.003cacaepumpdca_caepump/dt
0.003cacaepump - 288ca_caepump -
72ca_caepumpdca.plc_g/dt
0.8ca.plc_g_l.egfr 56pip2_ca.plc_g
14pip2_ca.plc_g 0.0003plc_gca
0.05ca.plc_g - 5e-06ca.plc_gl.egfr -
1.2e-06pip2ca.plc_g - 10ca.plc_gdl.egfr/d
t 0.8ca.plc_g_l.egfr 0.2ca.plc_g_l.egfr
0.8shc_l.egfr 0.2shc_l.egfr
7e-06egfregf 0.00033internal_l.egfr -
5e-06ca.plc_gl.egfr - 2e-06shcl.egfr -
0.25l.egfr - 0.002l.egfrdca.plc_g_l.egfr/dt
5e-06ca.plc_gl.egfr - 0.8ca.plc_g_l.egfr
- 0.2ca.plc_g_l.egfrdca.plc_g/dt
0.2ca.plc_g_l.egfr 228pip2_ca.plc_g
57pip2_ca.plc_g 2e-05caplc_g -
2.4e-05pip2ca.plc_g - 10ca.plc_g -
0.05ca.plc_gdshc/dt 0.8shc_l.egfr
0.0016667shc - 2e-06shcl.egfrdshc_l.egfr
/dt 2e-06shcl.egfr - 0.8shc_l.egfr -
0.2shc_l.egfrdshc/dt 0.2shc_l.egfr
0.1shc.sos.grb2 - 0.0016667shc -
8.333e-07sos.grb2shcdmapk/dt
0.6mapk_mapkk 1mapk-tyr_mkp-1 -
2.7e-05mapkmapkkdmapkk/dt
0.6mapk_mapkk 0.15mapk_mapkk
0.6mapk-tyr_mapkk 0.15mapk-tyr_mapkk
0.105mapkk-ser_raf-gtp-ras
25mapkk_pphosphatase2a - 2.7e-05mapkmapkk
- 2.7e-05mapk-tyrmapkk - 3.3e-06mapkkppho
sphatase2admapk_mapkk/dt
2.7e-05mapkmapkk - 0.6mapk_mapkk -
0.15mapk_mapkkdmapk-tyr/dt
0.15mapk_mapkk 0.6mapk-tyr_mapkk
4mapk-tyr_mkp-1 1mapk_mkp-1 -
2.7e-05mapk-tyrmapkk - 0.000125mapk-tyrmkp
-1dmapk-tyr_mapkk/dt 2.7e-05mapk-tyrmapk
k - 0.6mapk-tyr_mapkk - 0.15mapk-tyr_mapkk
dmapk/dt 0.15mapk-tyr_mapkk
80pla2-cytosolic_mapk 20pla2-cytosolic_mapk
40craf-1_mapk 10craf-1_mapk
40sos_mapk 10sos_mapk 4mapk_mkp-1 -
6.5e-06pla2-cytosolicmapk -
3.25e-06craf-1mapk - 3.25e-05sosmapk -
0.000125mapkmkp-1dmapkk/dt
0.42mapkk_raf-gtp-ras 6mapkk-ser_pphosphatas
e2a - 5.5e-06mapkkraf-gtp-rasdraf-gtp-ras
/dt 0.42mapkk_raf-gtp-ras
0.105mapkk_raf-gtp-ras 0.42mapkk-ser_raf-gtp
-ras 0.105mapkk-ser_raf-gtp-ras
4e-05craf-1gtp-ras - 5.5e-06mapkkraf-gtp-r
as - 5.5e-06mapkk-serraf-gtp-ras -
0.5raf-gtp-rasdmapkk_raf-gtp-ras/dt
5.5e-06mapkkraf-gtp-ras - 0.42mapkk_raf-gtp-
ras - 0.105mapkk_raf-gtp-rasdmapkk-ser/dt
0.105mapkk_raf-gtp-ras 0.42mapkk-ser_raf-g
tp-ras 6mapkk_pphosphatase2a
25mapkk-ser_pphosphatase2a - 5.5e-06mapkk-ser
raf-gtp-ras - 3.3e-06mapkk-serpphosphatase2a
dmapkk-ser_raf-gtp-ras/dt
5.5e-06mapkk-serraf-gtp-ras -
0.42mapkk-ser_raf-gtp-ras - 0.105mapkk-ser_raf
-gtp-rasdcraf-1/dt 16craf-1_pkc-dag-aa
16craf-1_pkc-ca-memb 16craf-1_pkc-ca-aa
16craf-1_pkc-dag-memb 16craf-1_pkc-basal
16craf-1_pkc-aa 6craf-1_pphosphatase2a
- 5e-07craf-1pkc-dag-aa - 5e-07craf-1pkc-c
a-memb - 5e-07craf-1pkc-ca-aa -
5e-07craf-1pkc-dag-memb - 5e-07craf-1pkc-b
asal - 5e-07craf-1pkc-aadpkc-dag-aa/dt
16craf-1_pkc-dag-aa 4craf-1_pkc-dag-aa
16gap_pkc-dag-aa 4gap_pkc-dag-aa
16inact-gef_pkc-dag-aa 4inact-gef_pkc-dag-aa
2pkc-dag-aa - 5e-07craf-1pkc-dag-aa -
1e-05gappkc-dag-aa - 1e-05inact-gefpkc-dag
-aa - 0.2pkc-dag-aadcraf-1_pkc-dag-aa/dt
5e-07craf-1pkc-dag-aa - 16craf-1_pkc-dag-a
a - 4craf-1_pkc-dag-aadcraf-1/dt
4craf-1_pkc-dag-aa 4craf-1_pkc-ca-memb
4craf-1_pkc-ca-aa 4craf-1_pkc-dag-memb
4craf-1_pkc-basal 4craf-1_pkc-aa
40craf-1_mapk 25craf-1_pphosphatase2a
6craf-1_pphosphatase2a 0.5raf-gtp-ras -
3.25e-06craf-1mapk - 3.3e-06craf-1pphosp
hatase2a - 4e-05craf-1gtp-rasdgap/dt
16gap_pkc-dag-aa 16gap_pkc-ca-memb
16gap_pkc-ca-aa 16gap_pkc-dag-memb
16gap_pkc-basal 16gap_pkc-aa
1000gtp-ras_gap 10gtp-ras_gap 0.1gap -
1e-05gappkc-dag-aa - 1e-05gappkc-ca-memb
- 1e-05gappkc-ca-aa - 1e-05gappkc-dag-mem
b - 1e-05gappkc-basal - 1e-05gappkc-aa
- 0.001666gtp-rasgapdgap_pkc-dag-aa/dt
1e-05gappkc-dag-aa - 16gap_pkc-dag-aa -
4gap_pkc-dag-aadgap/dt
4gap_pkc-dag-aa 4gap_pkc-ca-memb
4gap_pkc-ca-aa 4gap_pkc-dag-memb
4gap_pkc-basal 4gap_pkc-aa -
0.1gapdinact-gef/dt 16inact-gef_pkc-dag-a
a 16inact-gef_pkc-ca-memb
16inact-gef_pkc-ca-aa 16inact-gef_pkc-dag-me
mb 16inact-gef_pkc-basal
16inact-gef_pkc-aa 36inact-gef_pka-active
1gef-gprot-bg 1gef 1cam-gef
1inact-gef - 1e-05inact-gefpkc-dag-aa -
1e-05inact-gefpkc-ca-memb -
1e-05inact-gefpkc-ca-aa - 1e-05inact-gefpk
c-dag-memb - 1e-05inact-gefpkc-basal -
1e-05inact-gefpkc-aa - 1e-05inact-gefpka-a
ctive - 1e-05betagammainact-gef -
0.0001inact-gefcam-ca4dinact-gef_pkc-dag-aa
/dt 1e-05inact-gefpkc-dag-aa -
16inact-gef_pkc-dag-aa - 4inact-gef_pkc-dag-aa
dgef/dt 4inact-gef_pkc-dag-aa
4inact-gef_pkc-ca-memb 4inact-gef_pkc-ca-aa
4inact-gef_pkc-dag-memb
4inact-gef_pkc-basal 4inact-gef_pkc-aa
0.08gdp-ras_gef 0.02gdp-ras_gef -
3.3e-07gdp-rasgef - 1gefdpkc-ca-memb/d
t 16craf-1_pkc-ca-memb 4craf-1_pkc-ca-memb
16gap_pkc-ca-memb 4gap_pkc-ca-memb
16inact-gef_pkc-ca-memb 4inact-gef_pkc-ca-me
mb 1.2705pkc-ca - 5e-07craf-1pkc-ca-memb
- 1e-05gappkc-ca-memb - 1e-05inact-gefpk
c-ca-memb - 3.5026pkc-ca-membdcraf-1_pkc-ca
-memb/dt 5e-07craf-1pkc-ca-memb -
16craf-1_pkc-ca-memb - 4craf-1_pkc-ca-membd
gap_pkc-ca-memb/dt 1e-05gappkc-ca-memb
- 16gap_pkc-ca-memb - 4gap_pkc-ca-membdina
ct-gef_pkc-ca-memb/dt 1e-05inact-gefpkc-ca-
memb - 16inact-gef_pkc-ca-memb -
4inact-gef_pkc-ca-membdpkc-ca-aa/dt
16craf-1_pkc-ca-aa 4craf-1_pkc-ca-aa
16gap_pkc-ca-aa 4gap_pkc-ca-aa
16inact-gef_pkc-ca-aa 4inact-gef_pkc-ca-aa
2e-09pkc-caaa - 5e-07craf-1pkc-ca-aa
- 1e-05gappkc-ca-aa - 1e-05inact-gefpkc-ca
-aa - 0.1pkc-ca-aadcraf-1_pkc-ca-aa/dt
5e-07craf-1pkc-ca-aa - 16craf-1_pkc-ca-aa
- 4craf-1_pkc-ca-aadgap_pkc-ca-aa/dt
1e-05gappkc-ca-aa - 16gap_pkc-ca-aa -
4gap_pkc-ca-aa dglu/dt 10rec-glu
0.1rec-glu-gq - 2.8e-05mglurglu -
2.8e-05glurec-gqdrec-glu/dt
2.8e-05mglurglu 0.0001rec-glu-gq
0.01rec-glu-gq - 10rec-glu -
1e-08g-gdprec-gludg-gdp/dt
1e-05ggdpbetagamma 0.0001rec-glu-gq
1rec-gq - 0.0001g-gdp - 1e-08g-gdprec-glu
- 1e-06g-gdpmglurdggtp/dt 0.0001g-gdp
0.01rec-glu-gq 1plc-ca-gq 1plc-gq -
0.0133ggtp - 4.2e-05ggtpplc-ca -
4.2e-06plcggtpdbetagamma/dt
0.0001g-gdp 0.01rec-glu-gq
1gef-gprot-bg - 1e-05ggdpbetagamma -
1e-05betagammainact-gefdggdp/dt
0.0133ggtp 0.0133plc-ca-gq -
1e-05ggdpbetagammadrec-glu-gq/dt
1e-08g-gdprec-glu 2.8e-05glurec-gq -
0.0001rec-glu-gq - 0.1rec-glu-gq -
0.01rec-glu-gqdrec-gq/dt 0.1rec-glu-gq
1e-06g-gdpmglur 0.01blocked-rec-gq -
2.8e-05glurec-gq - 1rec-gq -
0.0001rec-gqmglurantagdmglurantag/dt
0.01blocked-rec-gq - 0.0001rec-gqmglurantag
dblocked-rec-gq/dt 0.0001rec-gqmglurantag
- 0.01blocked-rec-gqdpkc-cytosolic/dt
0.5pkc-ca 50pkc-basal 0.1pkc-aa
0.1pkc-dag - 1e-06pkc-cytosolicca -
1pkc-cytosolic - 2e-10aapkc-cytosolic -
1e-09pkc-cytosolicdagdpkc-ca/dt
1e-06pkc-cytosolicca 8.6348pkc-ca-dag
3.5026pkc-ca-memb 0.1pkc-ca-aa -
0.5pkc-ca - 1.3333e-08dagpkc-ca -
1.2705pkc-ca - 2e-09pkc-caaadpkc-ca-dag/d
t 1.3333e-08dagpkc-ca 0.1pkc-dag-memb
- 8.6348pkc-ca-dag - 1pkc-ca-dagdpkc-dag-aa
/dt 0.2pkc-dag-aa 3e-08pkc-dagaa -
2pkc-dag-aa - 2pkc-dag-aadpkc-dag/dt
1e-09pkc-cytosolicdag 2pkc-dag-aa -
0.1pkc-dag - 3e-08pkc-dagaadtemp-pip2/dt
0.5pip2-pla2 0.1pip2-ca-pla2 -
2e-09temp-pip2pla2-cytosolic -
2e-08temp-pip2pla2-cadplc/dt 1plc-ca
1plc-gq - 5e-06caplc - 4.2e-06plcggtp
dinositol/dt 2.5ip3dpc/dt
0.15dagdplc-gq/dt 4.2e-06plcggtp
1plc-ca-gq - 1plc-gq - 5e-05caplc-gqdplc
_g/dt 10ca.plc_g - 0.0003plc_gcadplc_g
/dt 10ca.plc_g - 2e-05caplc_gdcam-ca4
/dt 1cam-gef - 0.0001inact-gefcam-ca4ds
os.grb2/dt 0.1shc.sos.grb2
4.1667e-08grb2sos - 8.333e-07sos.grb2shc
- 0.0168sos.grb2dgrb2/dt 0.0168sos.grb2
0.0168sos.grb2 - 4.1667e-08sosgrb2 -
4.1667e-08grb2sosdsos.grb2/dt
4.1667e-08sosgrb2 - 0.0168sos.grb2dca-ex
t/dt 72ca_caepump - 0.005
capacitive_ca_entry ( ca-ext - ca ) -
0.004 ca-leak-from-extracell ( ca-ext -
ca ) dca-sequester/dt 25catransp-2ca
25catransp-2ca 1inact_cap_entry
1inact_cap_entry - 1.2e-11ca-sequesterca-sequ
estercapacitive_ca_entry - 1.2e-11ca-sequeste
rca-sequestercapacitive_ca_entry - 8
ca-leak-to-cytoplasm ( ca-sequester - ca
) - 19.2 ip3r ( ca-sequester - ca
)
dinact-gef_pkc-ca-aa/dt 1e-05inact-gefpkc-
ca-aa - 16inact-gef_pkc-ca-aa -
4inact-gef_pkc-ca-aadpkc-dag-memb/dt
16craf-1_pkc-dag-memb 4craf-1_pkc-dag-memb
16gap_pkc-dag-memb 4gap_pkc-dag-memb
16inact-gef_pkc-dag-memb 4inact-gef_pkc-dag-
memb 1pkc-ca-dag - 5e-07craf-1pkc-dag-mem
b - 1e-05gappkc-dag-memb -
1e-05inact-gefpkc-dag-memb -
0.1pkc-dag-membdcraf-1_pkc-dag-memb/dt
5e-07craf-1pkc-dag-memb - 16craf-1_pkc-dag-m
emb - 4craf-1_pkc-dag-membdgap_pkc-dag-memb
/dt 1e-05gappkc-dag-memb -
16gap_pkc-dag-memb - 4gap_pkc-dag-membdina
ct-gef_pkc-dag-memb/dt 1e-05inact-gefpkc-da
g-memb - 16inact-gef_pkc-dag-memb -
4inact-gef_pkc-dag-membdpkc-basal/dt
16craf-1_pkc-basal 4craf-1_pkc-basal
16gap_pkc-basal 4gap_pkc-basal
16inact-gef_pkc-basal 4inact-gef_pkc-basal
1pkc-cytosolic - 5e-07craf-1pkc-basal -
1e-05gappkc-basal - 1e-05inact-gefpkc-basa
l - 50pkc-basaldcraf-1_pkc-basal/dt
5e-07craf-1pkc-basal - 16craf-1_pkc-basal
- 4craf-1_pkc-basaldgap_pkc-basal/dt
1e-05gappkc-basal - 16gap_pkc-basal -
4gap_pkc-basaldinact-gef_pkc-basal/dt
1e-05inact-gefpkc-basal - 16inact-gef_pkc-ba
sal - 4inact-gef_pkc-basaldpkc-aa/dt
16craf-1_pkc-aa 4craf-1_pkc-aa
16gap_pkc-aa 4gap_pkc-aa
16inact-gef_pkc-aa 4inact-gef_pkc-aa
2e-10aapkc-cytosolic - 5e-07craf-1pkc-aa
- 1e-05gappkc-aa - 1e-05inact-gefpkc-aa
- 0.1pkc-aadcraf-1_pkc-aa/dt
5e-07craf-1pkc-aa - 16craf-1_pkc-aa -
4craf-1_pkc-aadgap_pkc-aa/dt
1e-05gappkc-aa - 16gap_pkc-aa -
4gap_pkc-aadinact-gef_pkc-aa/dt
1e-05inact-gefpkc-aa - 16inact-gef_pkc-aa
- 4inact-gef_pkc-aadapc/dt
21.6apc_pla2-ca 44.16apc_pip2-pla2
144apc_pip2-ca-pla2 240apc_dag-ca-pla2
480apc_pla2-ca 0.4aa - 2.25e-06apcpla2-c
a - 4.6e-06apcpip2-pla2 -
1.5e-05apcpip2-ca-pla2 - 2.5e-05apcdag-ca-
pla2 - 5e-05apcpla2-cadpla2-ca/dt
21.6apc_pla2-ca 5.4apc_pla2-ca
1.6667e-06pla2-cytosolicca
0.1pip2-ca-pla2 4dag-ca-pla2 -
2.25e-06apcpla2-ca - 0.1pla2-ca -
2e-08temp-pip2pla2-ca - 5e-09dagpla2-ca
dapc_pla2-ca/dt 2.25e-06apcpla2-ca -
21.6apc_pla2-ca - 5.4apc_pla2-cadaa/dt
5.4apc_pla2-ca 11.04apc_pip2-pla2
36apc_pip2-ca-pla2 60apc_dag-ca-pla2
120apc_pla2-ca 0.1pkc-ca-aa
0.1pkc-aa 2pkc-dag-aa - 2e-09pkc-caaa
- 2e-10aapkc-cytosolic - 3e-08pkc-dagaa -
0.4aadpip2-pla2/dt 44.16apc_pip2-pla2
11.04apc_pip2-pla2 2e-09temp-pip2pla2-cy
tosolic - 4.6e-06apcpip2-pla2 -
0.5pip2-pla2dapc_pip2-pla2/dt
4.6e-06apcpip2-pla2 - 44.16apc_pip2-pla2
- 11.04apc_pip2-pla2dpip2-ca-pla2/dt
144apc_pip2-ca-pla2 36apc_pip2-ca-pla2
2e-08temp-pip2pla2-ca - 1.5e-05apcpip2-ca-
pla2 - 0.1pip2-ca-pla2dapc_pip2-ca-pla2/d
t 1.5e-05apcpip2-ca-pla2 -
144apc_pip2-ca-pla2 - 36apc_pip2-ca-pla2dd
ag-ca-pla2/dt 240apc_dag-ca-pla2
60apc_dag-ca-pla2 5e-09dagpla2-ca -
2.5e-05apcdag-ca-pla2 - 4dag-ca-pla2dapc
_dag-ca-pla2/dt 2.5e-05apcdag-ca-pla2 -
240apc_dag-ca-pla2 - 60apc_dag-ca-pla2dpla
2-ca/dt 480apc_pla2-ca 120apc_pla2-ca
1e-05pla2ca - 5e-05apcpla2-ca -
0.1pla2-cadapc_pla2-ca/dt
5e-05apcpla2-ca - 480apc_pla2-ca -
120apc_pla2-cadpla2-cytosolic/dt
80pla2-cytosolic_mapk 0.1pla2-ca
0.5pip2-pla2 0.17pla2 -
6.5e-06pla2-cytosolicmapk -
1.6667e-06pla2-cytosolicca -
2e-09temp-pip2pla2-cytosolicdpla2-cytosolic_
mapk/dt 6.5e-06pla2-cytosolicmapk -
80pla2-cytosolic_mapk - 20pla2-cytosolic_mapk
dpla2/dt 20pla2-cytosolic_mapk
0.1pla2-ca - 1e-05pla2ca -
0.17pla2dcraf-1_mapk/dt
3.25e-06craf-1mapk - 40craf-1_mapk -
10craf-1_mapkdcraf-1/dt
10craf-1_mapk 25craf-1_pphosphatase2a -
3.3e-06craf-1pphosphatase2adsos/dt
40sos_mapk 0.001sos 0.0168sos.grb2 -
3.25e-05sosmapk - 4.1667e-08grb2sosdsos
_mapk/dt 3.25e-05sosmapk - 40sos_mapk
- 10sos_mapkdsos/dt 10sos_mapk
0.0168sos.grb2 - 4.1667e-08sosgrb2 -
0.001sosdmkp-1/dt 4mapk-tyr_mkp-1
1mapk-tyr_mkp-1 4mapk_mkp-1
1mapk_mkp-1 - 0.000125mapk-tyrmkp-1 -
0.000125mapkmkp-1dmapk-tyr_mkp-1/dt
0.000125mapk-tyrmkp-1 - 4mapk-tyr_mkp-1 -
1mapk-tyr_mkp-1dmapk_mkp-1/dt
0.000125mapkmkp-1 - 4mapk_mkp-1 -
1mapk_mkp-1dpphosphatase2a/dt
25craf-1_pphosphatase2a 6craf-1_pphosphatas
e2a 25mapkk_pphosphatase2a
6mapkk_pphosphatase2a 25mapkk-ser_pphosphata
se2a 6mapkk-ser_pphosphatase2a
25craf-1_pphosphatase2a 6craf-1_pphosphat
ase2a - 3.3e-06craf-1pphosphatase2a -
3.3e-06mapkkpphosphatase2a -
3.3e-06mapkk-serpphosphatase2a -
3.3e-06craf-1pphosphatase2adcraf-1_pphosp
hatase2a/dt 3.3e-06craf-1pphosphatase2a -
25craf-1_pphosphatase2a - 6craf-1_pphosphatas
e2admapkk_pphosphatase2a/dt
3.3e-06mapkkpphosphatase2a -
25mapkk_pphosphatase2a - 6mapkk_pphosphatase2
admapkk-ser_pphosphatase2a/dt
3.3e-06mapkk-serpphosphatase2a -
25mapkk-ser_pphosphatase2a - 6mapkk-ser_pphosph
atase2adcraf-1_pphosphatase2a/dt
3.3e-06craf-1pphosphatase2a -
25craf-1_pphosphatase2a - 6craf-1_pphosphat
ase2adpka-active/dt 36inact-gef_pka-active
9inact-gef_pka-active - 1e-05inact-gefpka-
activedinact-gef_pka-active/dt
1e-05inact-gefpka-active - 36inact-gef_pka-ac
tive - 9inact-gef_pka-activedinact-gef/dt
9inact-gef_pka-active - 1inact-gefdgdp-ra
s/dt 0.08gdp-ras_shc.sos.grb2
0.08gdp-ras_gef-gprot-bg 0.08gdp-ras_gef
10gtp-ras_gap 0.08gdp-ras_cam-gef
0.0001gtp-ras - 3.3e-07gdp-rasshc.sos.grb2
- 3.3e-07gdp-rasgef-gprot-bg -
3.3e-07gdp-rasgef - 3.3e-07gdp-rascam-gef
dshc.sos.grb2/dt 0.08gdp-ras_shc.sos.grb2
0.02gdp-ras_shc.sos.grb2
8.333e-07sos.grb2shc - 3.3e-07gdp-rasshc.
sos.grb2 - 0.1shc.sos.grb2dgdp-ras_shc.sos.
grb2/dt 3.3e-07gdp-rasshc.sos.grb2 -
0.08gdp-ras_shc.sos.grb2 - 0.02gdp-ras_shc.so
s.grb2dgtp-ras/dt 0.02gdp-ras_shc.sos.grb2
0.02gdp-ras_gef-gprot-bg
0.02gdp-ras_gef 1000gtp-ras_gap
0.02gdp-ras_cam-gef 0.5raf-gtp-ras -
0.001666gtp-rasgap - 4e-05craf-1gtp-ras
- 0.0001gtp-rasdpip2/dt 40pip2_plc-ca
192pip2_plc-ca-gq 56pip2_ca.plc_g
228pip2_ca.plc_g - 4.2e-06pip2plc-ca -
8e-05pip2plc-ca-gq - 1.2e-06pip2ca.plc_g
- 2.4e-05pip2ca.plc_gdplc-ca/dt
40pip2_plc-ca 10pip2_plc-ca
5e-06caplc 1plc-ca-gq 0.0133plc-ca-gq
- 4.2e-06pip2plc-ca - 1plc-ca -
4.2e-05ggtpplc-cadpip2_plc-ca/dt
4.2e-06pip2plc-ca - 40pip2_plc-ca -
10pip2_plc-caddag/dt 10pip2_plc-ca
48pip2_plc-ca-gq 14pip2_ca.plc_g
57pip2_ca.plc_g 8.6348pkc-ca-dag
0.1pkc-dag 4dag-ca-pla2 -
1.3333e-08dagpkc-ca - 1e-09pkc-cytosolicdag
- 5e-09dagpla2-ca - 0.15dagdip3/dt
10pip2_plc-ca 48pip2_plc-ca-gq
14pip2_ca.plc_g 57pip2_ca.plc_g 1ip3r
1ip3r 1ip3r - 1e-20ip3rip3ip3ip3
- 1e-20ip3rip3ip3ip3 -
1e-20ip3rip3ip3ip3 - 2.5ip3dplc-ca-gq
/dt 192pip2_plc-ca-gq 48pip2_plc-ca-gq
4.2e-05ggtpplc-ca 5e-05caplc-gq -
8e-05pip2plc-ca-gq - 1plc-ca-gq -
0.0133plc-ca-gq - 1plc-ca-gqdpip2_plc-ca-gq
/dt 8e-05pip2plc-ca-gq - 192pip2_plc-ca-gq
- 48pip2_plc-ca-gqdpip2_ca.plc_g/dt
1.2e-06pip2ca.plc_g - 56pip2_ca.plc_g -
14pip2_ca.plc_gdpip2_ca.plc_g/dt
2.4e-05pip2ca.plc_g - 228pip2_ca.plc_g -
57pip2_ca.plc_gdgef-gprot-bg/dt
0.08gdp-ras_gef-gprot-bg 0.02gdp-ras_gef-gpro
t-bg 1e-05betagammainact-gef -
3.3e-07gdp-rasgef-gprot-bg -
1gef-gprot-bgdgdp-ras_gef-gprot-bg/dt
3.3e-07gdp-rasgef-gprot-bg -
0.08gdp-ras_gef-gprot-bg - 0.02gdp-ras_gef-gpro
t-bgdgdp-ras_gef/dt 3.3e-07gdp-rasgef
- 0.08gdp-ras_gef - 0.02gdp-ras_gefdgtp-ra
s_gap/dt 0.001666gtp-rasgap -
1000gtp-ras_gap - 10gtp-ras_gapdcam-gef/dt
0.08gdp-ras_cam-gef 0.02gdp-ras_cam-gef
0.0001inact-gefcam-ca4 - 3.3e-07gdp-rascam-
gef - 1cam-gefdgdp-ras_cam-gef/dt
3.3e-07gdp-rascam-gef - 0.08gdp-ras_cam-gef
- 0.02gdp-ras_cam-gefdcatransp-2ca/dt
1e-08cacatranspca - 25catransp-2ca -
144catransp-2cadcatransp/dt
25catransp-2ca 144catransp-2ca -
1e-08cacatranspcadip3r/dt 1ip3r -
1e-20ip3rip3ip3ip3dinact_cap_entry/dt
1.2e-11ca-sequesterca-sequestercapacitive_c
a_entry - 1inact_cap_entrydegfr/dt
0.25l.egfr - 7e-06egfregfdegf/dt
0.25l.egfr - 7e-06egfregfdinternal_l.egfr
/dt 0.002l.egfr - 0.00033internal_l.egfrdm
glur/dt 10rec-glu 1rec-gq -
2.8e-05mglurglu - 1e-06g-gdpmglur
12
Parameters

• 1 Science. 1999 Jan 15283(5400)381-7.
• Emergent properties of networks of biological
  signaling pathways.Bhalla US, Iyengar R.

13
How may a mutation affect kinetics?
d
14
Effects on signaling
A mutation between two unique species Affects
Reactant State Affects Product State Affects
Transition State
15
Cancer as a cumulative process

• Multiple Mutations at different sites contribute
  to tumor transformation
• Tumor may exist as families of differentially
  mutated cells
• Overrides resistance of tumor
• to treatment

16
In Silico Interaction Knockout experiments
17
Single Site Transformations(kf/kf)
18
Top Ranked Mutations
X pp2a ? X.pp2a 0.75
X.pp2a ? X pp2a 0.75
raf gtp-ras ? raf.gtp.ras 0.60
Gtp-ras.gap ?gap gdp-ras 0.55
raf pp2a ?raf.pp2a 0.55
gtp-ras gap ? gtp.ras_gap 0.55
AA ? apc 0.55
Ca.CaPump ? capump ca-ext 0.55
X Raf.GTP.Ras ? X.Raf.GTP.Ras 0.50
PKC.DAG AA ? PKC.DAG.AA 0.50

19
Top Ranked expression level mutations
Species
Species
0.4 MKP-1
0.5 GAP
0.7 PP2-A
1.4 PKC-I
1.6 Raf
1.7 Ras
1.9 GEF
2.8 MEK
3.0 PLC
3.4 PLC-g
3.6 ERK
20
Advantages of In Silico Pathway Analysis

• Using experimentally validated models of a
  working
• signal pathway and a simple kinetic view of
  mutations
• One can
• Quantify (and rank)
• Single Interaction Mutations
• Multiple Interaction Mutations
• Initial State Mutations
• Many results are validated in the literature
• Several new and non-obvious predictions

21
In Silico Cancer Cells

• We have developed a family of in silico cancer
  cells as models of pathways
• What is this good for?

22
The effect of Drugs on Signaling in mutated cells
Competitive Binding
Noncompetitive binding
23
ERK Target
24
MEK Target
25
Calciumblockers
26
Threshold Ranking
27
Experimental Assays

• PLC-? - peptide based inhibitors
• PLC - U73122
• PKC - Tamoxifen , Go6976, SPC-100221
• PLA-2 - Quinacrine (anti-inflammatory)
• ERK -
• MEK - AZD6244/ARRY-142886, CI-1040 , PD98059
• Ras - R115577, BMS-214462 SCH-66336
• Raf - Bay43-9006 ISIS-5132
• GEF -
• Calcium Blockers Verapamil , Nicardipine

28
Overview

• Ras/Gap mutations predicted
• PP2A mutations predicted
• Ras/Raf interaction importance predicted
• Much of the overexpression/underexpression
• mutations predicted
• Drug targets are for the most part have
  experimental counter parts.

29
Transport?
30
How to treat real cells?
31
Confocal Imaging and Quantum Dots
(Andres Kriete)
QDots Tunable Photostable Narrow Emission
Spectra Broad Absorption Spectrum
Confocal Imaging Live Cells and fixed cells
sub micron imaging
32
Quantitative Signaling Analysis
Data from Confocal Imaging - derivation of
in vivo rate constants through global
analysis Given time sliced images and model
Derived rate constants will fit experimental
images best (global optimization problem)
with confidence intervals - wealth of data
helps prevent over fitting C(x,y,z,t) -
Automated Sensitivity Analysis will be used for
fitting
33
Cell(ular)Sim(ulator)

• Cross Platform (Linux, Windows, MacOS X, Solaris)
  
• Multiprocessor (MPI) (linear scaling)
• Freely Available (GPL)
• Pseudo-C Scripting Language
• Adaptive Integrators (Reaction Diffusion) with
  Sensitivity Analysis
• - (Adaptive 2nd and 4th order Rosenbrock,
  Euler RK2,RK4,ARK4)
• - Strang Split RDR Coupled Diffusion

34
Analysis Optimization Tools

• Sensitivity Analysis Module (Automatic generation
  of Jacobian, Hessian)
• MCA Module (Conservation Relationships)
• Global Optimization Tools
• - Use tools derived by the Protein Folding
  Community (and elsewhere)
• - Simulated Annealing
• - Monte Carlo Minimization
• - GA / Evolutionary Programming

35
Numerical Methods
Equations are stiff, Jacobian is Sparse
Reaction - Diffusion Reaction - Advection RADAR
Must ize well and must be accurate
36
Reaction Operator Rosenbrock
We have this for solving
Inherently for our distribution scheme
37
Diffusion Operator
Simple algorithm based on explicit (FTCS)
method Simple single processor method based on
Crank-Nicolson Crank-Nicolson method based on
the fact that you are solving a slew of
independent 1D tri-diagonal solves
38
Advection Operator
Based on Lax (explicit, inherently
) Nonlinear part of advection operator moved to
reaction Operator
39
Time Step Adaptability
Calculate the splitting error (and local errors)
use total error for estimating time step
Currently we have this for Reaction-Diffusion
40
Visualization
Cross Platform QT/OpenGL Code Base Client
/ Server (Socket Based) GUI Live Interaction
with Numerical Code 1D/2D/3D time lapse
contour plots Mouse-based interactive
manipulation Flexible Modular Design To Be
Implemented Point and Click graphical Entry
of Biological Pathways, Grid Geometry,
Initial Parameters and Control
41
Who did the real work?

• Dhruv Pant Ph.D.
• Dave Miller
• Ray Zou
• Yihua Wang
• Hanbing Lin
• Tom Shortell
• Travis Hoppe
• Aparna Kumar

http//bio.physics.drexel.edu http//bio.physics.d
rexel.edu/systemsBiology
Email avijit_at_physics.drexel.edu