shen_modules.py

[source]

Overview

PySB implementations of Bcl2-models from the group of Pingping Shen, along with other derived, closely related models.

In a series of papers from 2007-2010, the research group of Pingping Shen implemented and investigated models of Bcl-2 family interactions. In this file we have re-implemented these models using PySB. We have also included a model from [Howells2011] which is a fairly straightforward extension of a Shen group model from [Chen2007biophysj].

MOMP model implementations

The implementations of the various models are contained within the following functions:

Model descriptions (with references) are available in the documentation for each function.

The models are closely related, and many of the later models are derived from earlier ones. The models have been implemented in such a way as to make this hierarchy transparent.

Shared functions

In addition to the implementations of the models themselves, this file also contains two macros that are re-used by the various models:

  • momp_monomers(), which declares the Bcl-2 molecule types used in the models, and
  • shen_pore_transport(), which declares the set of transport reactions required for the release of Cytochrome c and Smac.

Parameter values

In the original papers, species quantities and forward rate constants were either given in units of micromolar ([Chen2007biophysj], [Howells2011]) or nanomolar ([Chen2007febs], [Cui2008]). For consistency, these values have been written in terms of their molar equivalents (for example, 0.1uM = 0.1e-6 M; 3 uM^-1 s^1 = 3e6 M^-1 s^-1). Concentrations have been converted into units of numbers of molecules according to:

No. of molecules = Conc * N_A * vol

where N_A is Avogadro’s number and vol is the cell volume, which is given a default value in the global variable V defined in shared.py. Similarly, forward rate constants are converted into stochastic rate constants according to:

Stoch. rate constant = Det. rate constant / (N_A * vol)

Functions

earm.shen_modules.momp_monomers()[source]

Declares the signatures of the Bcl-2 family monomers used in all of the Shen models.

In principle, each Shen MOMP model implementation could declare its own set of Bcl-2 monomers, each with its own site and state signature. In the interest of consistency, a unified set of monomer signatures that supports all of the models is defined here.

earm.shen_modules.shen_pore_transport(pore_size=4)[source]

Implements release of Cytochrome C and Smac.

Uses the same model as the original EARM 1.0 ([Albeck2008]), in which pore transport is modeled as binding of the cargo (cytochrome C or Smac) to the active pore, and then release, in a catalysis-like mechanism.

The initial conditions for cytochrome C and Smac, and the rate constants for transport, are also taken from EARM 1.0.

earm.shen_modules.chen_biophys_j(do_pore_assembly=True, do_pore_transport=False)[source]

Model drawn from [Chen2007biophysj].

Model features (see the source code):

  • Activation of Bax by an activator (tBid) in a one-step, hit-and-run manner; Bax activation is reversible.
  • Bcl2 binds both tBid and Bax Bax can displace tBid from Bcl-2 (but not the reverse).
  • If Bax oligomerization is incorporated into the model (see do_pore_assembly argument, below), then this occurs as a spontaneous, order 4 reaction.

This model combines both “direct” type and “indirect” type elements in that Bcl-2 is capable of binding both Bid and Bax (see bind_table call in the source code).

Parameters:

do_pore_assembly : True (default) or False

If True, adds the formation of Bax oligomers to the model. If False, the model’s most downstream element is Bax activation. This is included for two reasons: first, the original publication included two variant models, one with and one without Bax oligomerization, so this allows this aspect of the original models to be explored. Second, it allows a model that extends this model to implement a different model of Bax pore assembly (for example, as is the case with cui_direct).

do_pore_transport : True or False (default)

If True, adds the release of Cytochrome C and Smac to the model by calling the function shen_pore_transport(). If CytoC/Smac release are not incorporated into the model, the model matches the originally published model but can’t be composed into the full extrinsic apoptosis pathway.
earm.shen_modules.chen_febs_indirect(do_pore_assembly=True, do_pore_transport=False)[source]

The “indirect” model drawn from [Chen2007febs].

Model features (see the source code):

  • There is no activation of Bax by tBid. Bax starts out constitutively “active” in that in its initial state, it is able to form oligomers.
  • Bcl-2 can bind tBid and Bax.
Parameters:

do_pore_assembly : True (default) or False

do_pore_transport : True or False (default)
earm.shen_modules.chen_febs_direct(do_pore_assembly=True, do_pore_transport=False)[source]

The “direct” model drawn from [Chen2007febs].

Model features (see the source code):

  • Activation of Bax by an activator (tBid) in a one-step, hit-and-run manner; Bax activation is reversible.
  • Bcl-2 can bind tBid, but not Bax.
Parameters:

do_pore_assembly : True (default) or False

do_pore_transport : True or False (default)
earm.shen_modules.cui_direct(do_pore_transport=False)[source]

The “direct” model drawn from [Cui2008].

Builds on the direct model from [Chen2007febs], implemented in chen_febs_direct() (see source code).

Parameters:

do_pore_transport : True or False (default)
earm.shen_modules.cui_direct1(do_pore_transport=False)[source]

The “direct 1” model drawn from [Cui2008].

Builds on the (base) direct model from [Cui2008], implemented in cui_direct() (see source code).

Parameters:

do_pore_transport : True or False (default)
earm.shen_modules.cui_direct2(do_pore_transport=False)[source]

The “direct 2” model drawn from [Cui2008].

Builds on the “direct 1” model from [Cui2008], implemented in cui_direct1() (see source code).

Parameters:

do_pore_transport : True or False (default)
earm.shen_modules.howells(do_pore_assembly=True, do_pore_transport=False)[source]

The model drawn from [Howells2011].

This model builds on the model from [Chen2007biophysj], implemented in chen_biophys_j(). The core reactions from the Chen et al. model are the same, but Howells et al. modify some parameter values and add a number of Bad-related reactions, including (see source code):

  • Unphosphorylated Bad spontaneously translocates between cytosol and mitochondria
  • Bad binds Bcl-2
  • Bad displaces tBid from Bcl-2
  • Cytosolic, mitochondrial, and Bad in a mitochondrial Bad:Bcl2 complex can be phosphorylated at various rates (this is modeled as a first-order reaction with no explicit representation of kinases)
  • Bad can be sequestered by, and released from, 14-3-3 domains in the cytosol (modeled as a first-order reaction with no explicit representation of 14-3-3-domain-containing proteins)
Parameters:

do_pore_assembly : True (default) or False

do_pore_transport : True or False (default)