Supplementary Information
Table S1: Description of key nodes of the model.
Node
Hsp90-CDC37
binding
Equation
CDC37 + Hsp90 =
Hsp90_CDC37
Mechanism and Assumption
References
This is modeled as reversible (Siligardi et al.
mass action kinetics
2004; Zhang et
The Kd for the interaction of al. 2004; Roe et
CDC37 and Hsp90 has been
al. 2004)
taken as 2.5uM
Hsp90-CDC37
Hsp90_CDC37 +
This is modeled as reversible
(Lawlor and
complex
AKT1_Par_Act =
mass action kinetics
Alessi, 2004;
binding to Hsp90_CDC37_AKT1
The kinetics has been
Schulte et al.
AKT1
_Par_Act
optimized. It has been assumed
1995)
that Hsp90 binds to all the
protein kinases with the same
affinity.
Hsp90-ATP- Hsp90_ATP_AKT1_P This is modeled as reversible
(Kamal et al.
AKT1
ar_Act = AKT1_Act +
mass action kinetics
2004)
hydrolysis
Pi + Hsp90_ADP
The value for kf has been
optimized to 0.15 sec-1 as
against 1.5E-3 sec-1 as
mentioned in the literature and
the value of Kr has also been
optimized
Hsp90-CDC37- Hsp90_CDC37 +
This is modeled as reversible
(Kamal et al.
RAF1 binding
RAF1 =
mass action kinetics
2003; Roe et al.
Hsp90_CDC37_RAF1 The binding affinity for all the
2004)
protein kinase to the
Hsp90_CDC37 complex has
been assumed to be same.
ATP binding to Hsp90_CDC37_RAF1 This is modeled as reversible (Sato et al. 2000;
the Hsp90+ ATP =
mass action kinetics
Roe et al. 2004)
CDC37-RAF1 Hsp90_ATP_RAF1 + This is the reaction node where
complex
CDC37
the generic inhibitor would act
HRAS-GTP Hsp90_ATP_RAF1 = This is modeled as a modified (Kholodenko,
mediated
Hsp90_ATP_RAF1p Michaelis Menten reaction.
2000)
activation of
RAF1
Hsp90
Hsp90 = Hsp90_Da
This is modeled as a simple
(Yang et al.
deacetylation by
Michealis Menton equation
2006)
HDAC6
The Km and Kcat values have
been assumed.
Deacetylated Hsp90_Da + EGFR = This is modeled as reversible
Hsp90 binding Hsp90_Da_EGFR
mass action kinetics
(Yang et al.
2006)
Node
to EGFR
Equation
Mechanism and Assumption
The Kinetic parameters have
been optimized. It has been
assumed that all the growth
factors bind to Hsp90 with the
same binding affinities with a
Kd of 0.02 uM. The value of
Kd has been optimized
References
EGFR-EGFL6
binding
EGFL6 + EGFR =
EGFL6_EGFR
This is modeled as reversible
mass action kinetics
(Kholodenko,
2000)
Hsp90 binding
to IGF-1R
Hsp90 + IGF1R =
IGF1R_Hsp90
IGF-1R binding
to its ligand
IGF1
IGF1R + IGF1 =
IGF1_IGF1R
This is modeled as reversible (Di Paola et al.
mass action kinetics
2006)
It has been assumed that all the
growth factors bind to Hsp90
with the same binding affinities
with a Kd of 0.02 uM. The
value of Kd has been
optimized.
This is modeled as reversible
mass action kinetics
(Kholodenko,
here the data are taken as same
2000)
as that of EGF binding to its
receptor.
This is modeled as modified (Rui et al. 2001)
Michaelis Menten reaction
IGF1-IGF-1R
IRS = IRSp
mediated
activation and
The kinetics have been
phosphorylation
assumed
of IRS
IRSp binding to PIK3R1_InAct + IRSp This is modeled as reversible (Kim et al. 1999)
PI3k and
=
mass action kinetics
activation
PI3KR1_InAct_IRSp
Hsp90 binding Hsp90 + ERBB2_Inact This is modeled as reversible
to
=
mass action kinetics
HER2/ERBB2 Hsp90_ERBB2_Inact
Hsp90-ATP
binding
Hsp90 + ATP =
Hsp90_ATP
(Hellyer et al.
2001)
Bi-substrate Michaelis Menten (McLaughlin et
reaction
al. 2002;
Siligardi et al.
2002; Banerji et
al. 2005)
Node
Equation
Mechanism and Assumption
References
Hsp90-ATP
IP + p23 +
This is modeled as reversible (Pratt and Toft,
complex
Hsp90_ATP =
mass action kinetics
2003)
binding to p23 Hsp90_ATP_p23_IP The kinetics has been assumed
and
immunophilin
Hsp70 binding
ATP + Hsp70 =
This is modeled as reversible (Pratt and Toft,
to ATP
Hsp70_ATP
mass action kinetics
2003)
The kinetics has been assumed
Hsp40 binding
Hsp40 +HIP=
This is modeled as reversible (Pratt and Toft,
to HIP
HSp40_HIP
mass action kinetics
2003)
The kinetics has been assumed
Hsp40-Hip
Hsp40_HIP +
complex
Hsp70_ATP =
binding to Hsp40_HIP_Hsp70_A
Hsp70-ATP
DP
complex
Hsp70-HipHsp90_HOP +
Hsp40 complex Hsp40_Hip_Hsp70_A
binding to
DP =
Hsp90 bound to Hsp90_HOP_Hsp70_
HOP
Hsp40_Hip
Hsp90-Hsp70 Hsp90_ATP_Hsp70_
complex
Hsp40 + mTP53c =
binding to
Hsp90_ATP_Hsp70_
mutant TP53
Hsp40_mTP53c
This is modeled as reversible
mass action kinetics
This binding activates the
ATPase activity for Hsp70
This is modeled as reversible
mass action kinetics
This binding activates the
ATPase activity for Hsp70
This is modeled as reversible
mass action kinetics
It has been assumed that p53
also binds to Hsp90 with the
same affinity as AKT or RAF1
P23 and IP
Hsp90_ATP_Hsp70_ This is modeled as reversible
binding to the Hsp40_TP53c + p23 +
mass action kinetics
Hsp90-hsp70Cyp40 = Hsp40 +
The Kd for the interaction of
mTP53 complex
Hsp70 +
p23 with Hsp90 is 1.5 uM.
Hsp90_ATP_TP53c_p This interaction results in the
23_Cyp40
formation of the mature
complex
Hsp90 binding
Hsp90_CDC37 +
This is modeled as reversible
to CDK4
CDK4 =
mass action kinetics
Hsp90_CDC37_CDK4 It has been assumed that
CDK4 also binds to Hsp90
with the same affinity as AKT
or RAF1
List of Abbreviations:
ATP – Adenosine tri phosphate
(Pratt and Toft,
2003)
(Pratt and Toft,
2003)
(Pratt and Toft,
2003)
(Siligardi et al.
2004)
(Siligardi et al.
2002; Banerji et
al. 2005;
Stepanova et al.
1996)
ADP – Adenosine di phosphate
Pi – Inorganic phosphate
Hsp90 - Heat shock protein 90
Hsp70 - Heat shock protein 70
Hsp40 - Heat shock protein 40
HIP- Hsp70 interacting protein
HOP: Hop factor
IP – immunophilins
CDC37 - cell division cycle 37 homolog
CCND1 – CyclinD1
TP53 – p53 Tumor suppressor protein
mTP53 – mutant TP53
EGFR – Epidermal growth factor receptor
IGF-1R – Insulin growth factor receptor-1
HER2/ ERBB2 - Human Epidermal growth factor Receptor 2
CDK4 - Cyclin dependent kinase 4
IRS – Insulin receptor substrate
RAF1 - v-raf-1 murine leukemia viral oncogene homolog 1