SUPPLEMENTARY MATERIALS

Table S1. Sensitivity analysis for the parameters in mitochondria-dependent apoptosis model. Steady-state values of caspase-3 when the parameters are perturbed

Parameters / [caspase-3] (nM)
parameter value x 100 / parameter value / 100
kd / 0 / 4827
ΩApaf-1 / 7 / 0
ΩIAP / 0 / 5
Ωprocaspase3 / 543 / 0
Ωprocaspase9 / 47 / 0
ΩBid / 2 / 0
ΩBcl2o / 0 / 6
ΩBaxo / 6 / 0
Ωcytcmito / 7 / 0
p53 / 6 / 0

Table S2. The parameter sets used in simulations of mitochondria-dependent apoptosis model for statistical evaluation (unit is nM/s throughout the table)

Variation
1A / Variation
1B / Variation
1C / Variation
1D / Variation
1E / Variation
1F
ΩIAP / 2.85x10-2 / 2.80x10-2 / 3.82x10-2 / 1.66x10-2 / 2.41x10-2 / 4.19x10-2
Ωprocasp3 / 1.65x10-1 / 1.42x10-1 / 2.98x10-1 / 1.41x10-1 / 2.94x10-1 / 1.94x10-1
Ωprocasp9 / 4.59x10-1 / 3.29x10-1 / 3.17x10-1 / 3.71x10-1 / 2.31x10-1 / 5.18x10-1
Ωcytcmito / 3.54x10-1 / 4.54x10-1 / 3.11x10-1 / 2.84x10-1 / 2.60x10-1 / 2.17x10-1
Variation
3A / Variation
3B / Variation
3C / Variation
3D / Variation
3E / Variation
3F
ΩIAP / 1.00x10-1 / 8.39x10-2 / 9.33x10-2 / 8.81x10-2 / 1.03x10-1 / 1.06x10-1
Ωprocasp3 / 7.77x10-1 / 9.13x10-1 / 8.86x10-1 / 1.07 / 8.85x10-1 / 9.57x10-1
Ωprocasp9 / 2.92x10-1 / 2.32x10-1 / 3.29x10-1 / 2.29x10-1 / 3.73x10-1 / 3.67x10-1
Ωcytcmito / 1.90x10-1 / 1.06x10-1 / 2.25x10-1 / 2.14x10-1 / 1.06x10-1 / 1.26x10-1

Table S3. Confidence intervals for the difference in the means of kd value for apoptosis induction for parameter sets 1 and 3.

Deficiency in proapoptotic
protein (nominal value multiplied by a factor) / Parameter set 1
Variation 1A
Variation 1B
Variation 1C
Variation 1D
Varitation 1E
Varitation 1F / Parameter set 3
Variation 3A
Variation 3B
Variation 3C
Variation 3D
Variation 3E
Variation 3F / Difference in means for
90% confidence interval
95% confidence interval
99% confidence interval
ΩApaf-1 x 0.01 / 0.35
0.36
0.37
0.35
0.33
0.32
0.32 / 0.27
0.32
0.26
0.35
0.33
0.28
0.29 / 0.0060 £ (m1-m3) £ 0.0633
0.0019 £ (m1-m3) £ 0.0698
-0.0082 £ (m1-m3) £ 0.0782
Ωprocaspase-3 x 0.01 / 0.31
0.21
0.19
0.30
0.19
0.28
0.25 / 0.53
0.49
0.49
0.54
0.53
0.55
0.57 / 0.2471 £ (m1-m3) £ 0.3349
0.2370 £ (m1-m3) £ 0.3450
0.2240 £ (m1-m3) £ 0.3580
Ωprocaspase-9 x 0.01 / 0.42
0.39
0.33
0.42
0.35
0.37
0.43 / 0.50
0.53
0.48
0.58
0.54
0.53
0.55 / 0.0687 £ (m1-m3) £ 0.2245
0.0508 £ (m1-m3) £ 0.2424
0.0277 £ (m1-m3) £ 0.2655
ΩBid x 0.01 / 0.88
0.90
0.90
0.89
0.85
0.84
0.85 / 0.79
0.86
0.77
0.90
0.87
0.80
0.83 / -0.0016 £ (m1-m3) £ 0.0684
-0.0096 £ (m1-m3) £ 0.0764
-0.0199 £ (m1-m3) £ 0.0867
ΩBax x 0.01 / 0.42
0.43
0.43
0.41
0.40
0.39
0.39 / 0.36
0.40
0.35
0.41
0.40
0.37
0.38 / -0.0475 £ (m1-m3) £ 0.0946
-0.0638 £ (m1-m3) £ 0.1104
-0.0848 £ (m1-m3) £ 0.1314
Ωcytcmito x 0.01 / 0.35
0.36
0.37
0.35
0.33
0.32
0.32 / 0.27
0.32
0.32
0.35
0.33
0.28
0.29 / 0.0024 £ (m1-m3) £ 0.0510
-0.0023 £ (m1-m3) £ 0.0557
-0.0103 £ (m1-m3) £ 0.0637
ΩApaf-1 x 0.15 / 0.78
0.82
0.83
0.79
0.74
0.72
0.74 / 0.62
0.73
0.60
0.79
0.75
0.64
0.68 / 0.0114 £ (m1-m3) £ 0.1386
-0.0032 £ (m1-m3) £ 0.1532
-0.0220 £ (m1-m3) £ 0.1720
Ωprocaspase-3 x 0.15 / 0.95
0.91
0.78
0.96
0.79
0.87
0.93 / 0.90
Healthy cell
0.88
Healthy cell
Healthy cell
0.94
0.98
Ωprocaspase-9 x 0.15 / 0.91
0.91
0.81
0.92
0.81
0.83
0.89 / 0.81
0.93
0.79
Healthy cell
0.95
0.84
0.88
ΩBid x 0.15 / Healthy cell
Healthy cell
Healthy cell
Healthy cell
Healthy cell
Healthy cell
Healthy cell / 0.97
Healthy cell
0.95
Healthy cell
Healthy cell
Healthy cell
Healthy cell
ΩBax x 0.15 / 0.94
0.96
0.75
0.94
0.90
0.88
0.90 / 0.81
0.90
0.79
0.94
0.91
0.84
0.86 / -0.0520 £ (m1-m3) £ 0.0820
-0.0674 £ (m1-m3) £ 0.0974
-0.0873 £ (m1-m3) £ 0.1173
Ωcytcmito x 0.15 / 0.78
0.82
0.65
0.79
0.74
0.72
0.74 / 0.62
0.73
0.60
0.79
0.75
0.64
0.68 / -0.024 £ (m1-m3) £ 0.01140
-0.0399 £ (m1-m3) £ 0.1299
-0.0603 £ (m1-m3) £ 0.1503

Table S4. Bcl-2 production rate constant range in which apoptosis occurs and possible other outcomes of explicit Bcl-2 inhibitor treatment

Deficiency in proapoptotic
protein (nominal value multiplied by a factor) / Parameter
set 1 / Parameter
set 2 / Parameter
set 3
ΩApaf-1 x 0.01 / x *
[caspase-3] = 0 nM / x
[caspase-3] = 0 nM / x
[caspase-3] = 0 nM
Ωprocaspase-3 x 0.01 / X
[caspase-3] = 0 nM / x
[caspase-3] = 0 nM / x
[caspase-3] = 0 nM
Ωprocaspase-9 x 0.01 / X
[caspase-3] = 0 nM / x
[caspase-3] = 0 nM / x
[caspase-3] = 0 nM
ΩBid x 0.01 / X
[caspase-3] = 0 nM / x
[caspase-3] = 0 nM / x
[caspase-3] = 0 nM
ΩBax x 0.01 / X
[caspase-3] = 0 nM / x
[caspase-3] = 0 nM / x
[caspase-3] = 0 nM
Ωcytcmito x 0.01 / X
[caspase-3] = 0 nM / x
[caspase-3] = 0 nM / x
[caspase-3] = 0 nM
ΩBcl2 x 400 / 2.5 mM Bcl-2 inh / 2.8 mM Bcl-2 inh / 33.1 mM Bcl-2 inh
ΩIAP x 400 / X
[caspase-3] = 0 nM / x
[caspase-3] = 0 nM / x
[caspase-3] = 0 nM
ΩApaf-1 x 0.15 / X
[caspase-3] = 0 nM / x
[caspase-3] = 0 nM / x
[caspase-3] = 0 nM
Ωprocaspase-3 x 0.15 / X
[caspase-3] = 0.80nM / x
[caspase-3] = 0.91nM / x
[caspase-3] = 0 nM
Ωprocaspase-9 x 0.15 / x
[caspase-3] = 0.52nM / x
[caspase-3] = 0.61nM / x
[caspase-3] = 0 nM
ΩBid x 0.15 / Healthy cell / Healthy cell / x
[caspase-3] = 0 nM
ΩBax x 0.15 / 0.4 mM Bcl-2 inh / 0.2 mM Bcl-2 inh / x
[caspase-3] = 0 nM
Ωcytcmito x 0.15 / X
[caspase-3] = 0 nM / x
[caspase-3] = 0 nM / x
[caspase-3] = 0 nM
ΩBcl2 x 200 / 1.0 mM Bcl-2 inh / 1.1 mM Bcl-2 inh / 20.9 mM Bcl-2 inh
ΩIAP x 200 / Healthy cell / Healthy cell / Healthy cell
ΩBcl2 x 10 / Healthy cell / Healthy cell / 0.8 mM Bcl-2 inh
ΩIAP x 10 / Healthy cell / Healthy cell / Healthy cell

* x: Apoptosis impossible even with very high Bcl-2 inhibitor initial concentration

Table S5. Possible outcomes of explicit IAP inhibitor treatment

Deficiency in proapoptotic
protein (nominal value multiplied by a factor) / Parameter
set 1 / Parameter
set 2 / Parameter
set 3
ΩApaf-1 x 0.01 / x *
[caspase-3] = 0 nM / x
[caspase-3] = 0 nM / x
[caspase-3] = 0 nM
Ωprocaspase-3 x 0.01 / x
[caspase-3] = 0 nM / x
[caspase-3] = 0 nM / x
[caspase-3] = 0 nM
Ωprocaspase-9 x 0.01 / x
[caspase-3] = 0 nM / x
[caspase-3] = 0 nM / x
[caspase-3] = 0 nM
ΩBid x 0.01 / x
[caspase-3] = 0 nM / x
[caspase-3] = 0 nM / x
[caspase-3] = 0 nM
ΩBax x 0.01 / x
[caspase-3] = 0 nM / x
[caspase-3] = 0 nM / x
[caspase-3] = 0 nM
Ωcytcmito x 0.01 / x
[caspase-3] = 0 nM / x
[caspase-3] = 0 nM / x
[caspase-3] = 0 nM
ΩBcl2 x 400 / x
[caspase-3] = 0 nM / x
[caspase-3] = 0 nM / x
[caspase-3] = 0 nM
ΩIAP x 400 / 30 mM IAP to restore apoptosis / 25 mM IAP to restore apoptosis / 110 mM IAP to restore apoptosis
ΩApaf-1 x 0.15 / x
[caspase-3] = 0 nM / x
[caspase-3] = 0 nM / x
[caspase-3] = 0 nM
Ωprocaspase-3 x 0.15 / x
[caspase-3]=0.79 nM / x
[caspase-3]=0.90 nM / x
[caspase-3] = 0 nM
Ωprocaspase-9 x 0.15 / x
[caspase-3]=0.48 nM / x
[caspase-3]=0.55 nM / x
[caspase-3] = 0 nM
ΩBid x 0.15 / Healthy cell / Healthy cell / x
[caspase-3] = 0 nM
ΩBax x 0.15 / x
[caspase-3] = 0 nM / x
[caspase-3] = 0 nM / x
[caspase-3] = 0 nM
Ωcytcmito x 0.15 / x
[caspase-3] = 0 nM / x
[caspase-3] = 0 nM / x
[caspase-3] = 0 nM
ΩBcl2 x 200 / x
[caspase-3] = 0 nM / x
[caspase-3] = 0 nM / x
[caspase-3] = 0 nM
ΩIAP x 200 / Healthy cell / Healthy cell / Healthy cell
ΩBcl2 x 10 / Healthy cell / Healthy cell / x
[caspase-3] = 0 nM
ΩIAP x 10 / Healthy cell / Healthy cell / Healthy cell

* x: Apoptosis is impossible even if IAP inhibitor initial concentration is very high

Figure S1. Vertical axis: steady state caspase-3 concentration for sensitive parameters A) kd, B) ΩApaf-1, C) ΩIAP D) Ωprocaspase3, E) Ωprocaspase9, F) ΩBid, G) ΩBcl2o, H) ΩBaxo, I) Ωcytcmito, J) p53. Horizontal axis: ratio of the parameter value to its nominal value (R). R = 1 corresponds to the nominal values of the parameters. As expected some curves are linear and some nonlinear. Malfunction in apoptosis (zero caspases-3 concentration) can be obtained in all figures.

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