<commit_before>Ras activity and regulation
===========================

Anatomy of Ras
--------------

For a diagram of the primary structure of Ras, see
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3915522/figure/F1/).::

    from pysb.macros import bind, bind_table

    # All of the Ras proteins have the following structural/regulatory features:
    for ras_name in ['KRAS', 'NRAS', 'HRAS']:
        Monomer(ras_name,
                ['gtp', 'gef', 'p_loop', 'switch1', 'switch2', 'CAAX', 'oncogenic'],
                {'oncogenic': ['y', 'n']})

    # Guanine nucleotides
    Monomer('GTP', ['p'])
    Monomer('GDP', ['p'])

A note on alternative splice variants:

    [3304147]_: The three functional ras genes code for highly related proteins
    generically known as p21 (71). The p21 coding sequences of each of these
    genes are equally distributed in four exons except for the K-ras-2 gene,
    which possesses two alternative fourth coding exons (exons IVA and IVB)
    that allow the synthesis of two isomorphic p21 proteins of 188 and 189
    residues that differ in their carboxy terminal domains (54, 60, 72).

Ras proteins are GTPases
------------------------

    [3304147]_: ras proteins, independently of their phylogenetic origin, have been
    shown to bind guanine nucleotides (GTP and GDP) ([3304147_22]_ [3304147_23]_
    [3304147_24]_ [3304147_25]_) and possess intrinsic GTPase activity
    ([3304147_25]_ [3304147_26]_ [6147754]_ [6148703]_ [3304147_29]_)

::

    def ras_interactions(ras):
        ras_binds_gtp_and_gdp(ras)
        ras_converts_gtp_to_gdp(ras)

Ras binds GTP and GDP
~~~~~~~~~~~~~~~~~~~~~

Mechanism and rates associated with GTP/GDP binding by Ras.

The following statements were taken from a kinetic analysis of Ras and
nucleotide interactions. All rates were measured at 20C.

    [9585556]_: the intrinsic dissociation rate of Ras for GTP (1 × 10-5 s-1) is
    2-fold lower than that for GDP (2 × 10-5 s-1)...

    [9585556]_: Numerically, it was more convenient to use the corresponding
    differential equations with the program FACSIMILE and to calculate for 1000
    s with the assumption of fast association rate constants (in all cases:
    10^7 M-1 s-1).

    [9585556]_: The equilibrium dissociation constant for Ras-3′mdGDP (KD1) had
    been determined independently as 9 pM from nucleotide association and
    dissociation experiments (Tables 2 and 3).

::

    # Make the same assumptions about fast association rate constants as 9585556,
    # and use their measured values for dissociation rates in the absence of GEFs.
    # (association rates are in units of nM^-1 s^-1).
    def ras_binds_gtp_and_gdp(ras):
        kf = 1e-2
        bind_table([[             GTP,         GDP],
                    [ras,  (kf, 1e-5),  (kf, 2e-5)]], 'gtp', 'p')

Ras converts GTP to GDP
~~~~~~~~~~~~~~~~~~~~~~~

GTP hydrolysis by wild-type Ras is very slow in the absence of RasGAPs.

    [1569940]_: It has been reported that the in vitro GTPase activity of wild-type
    p21, which proceeds at a rate of 0.028 min^-1 at 37°C ([2502546]_), is
    accelerated 100- to 200-fold by GAP, as measured under nonsaturating
    conditions.

::

    # Convert 2.8e-2 min^-1 to units of s^-1
    wt_ras_hydrolysis_rate = 2.8e-2 * 60

    def ras_converts_gtp_to_gdp(ras):
        k = Parameter('k_{0}_gtpase'.format(ras.name), 1.)
        Rule('{0}_converts_GTP_GDP'.format(ras.name),
             ras(gtp=1) % GTP(p=1) >>
             ras(gtp=1) % GDP(p=1),
             k)

    ras_interactions(KRAS)


Ras regulation by GEFs<commit_msg>Dissoc rates of Ras from GDP (Lenzen Table 1)<commit_after>Ras activity and regulation
===========================

Anatomy of Ras
--------------

For a diagram of the primary structure of Ras, see
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3915522/figure/F1/).::

    from pysb.macros import bind, bind_table

    # All of the Ras proteins have the following structural/regulatory features:
    for ras_name in ['KRAS', 'NRAS', 'HRAS']:
        Monomer(ras_name,
                ['gtp', 'gef', 'p_loop', 'switch1', 'switch2', 'CAAX', 'oncogenic'],
                {'oncogenic': ['y', 'n']})

    # Guanine nucleotides
    Monomer('GTP', ['p'])
    Monomer('GDP', ['p'])

A note on alternative splice variants:

    [3304147]_: The three functional ras genes code for highly related proteins
    generically known as p21 (71). The p21 coding sequences of each of these
    genes are equally distributed in four exons except for the K-ras-2 gene,
    which possesses two alternative fourth coding exons (exons IVA and IVB)
    that allow the synthesis of two isomorphic p21 proteins of 188 and 189
    residues that differ in their carboxy terminal domains (54, 60, 72).

Ras proteins are GTPases
------------------------

    [3304147]_: ras proteins, independently of their phylogenetic origin, have been
    shown to bind guanine nucleotides (GTP and GDP) ([3304147_22]_ [3304147_23]_
    [3304147_24]_ [3304147_25]_) and possess intrinsic GTPase activity
    ([3304147_25]_ [3304147_26]_ [6147754]_ [6148703]_ [3304147_29]_)

::

    def ras_interactions(ras):
        ras_binds_gtp_and_gdp(ras)
        ras_converts_gtp_to_gdp(ras)

Ras binds GTP and GDP
~~~~~~~~~~~~~~~~~~~~~

Mechanism and rates associated with GTP/GDP binding by Ras.

The following statements were taken from a kinetic analysis of Ras and
nucleotide interactions. All rates were measured at 20C.

    [9585556]_: the intrinsic dissociation rate of Ras for GTP (1 × 10-5 s-1) is
    2-fold lower than that for GDP (2 × 10-5 s-1)...

    [9585556]_: Numerically, it was more convenient to use the corresponding
    differential equations with the program FACSIMILE and to calculate for 1000
    s with the assumption of fast association rate constants (in all cases:
    10^7 M-1 s-1).

    [9585556]_: The equilibrium dissociation constant for Ras-3′mdGDP (KD1) had
    been determined independently as 9 pM from nucleotide association and
    dissociation experiments (Tables 2 and 3).



::

    # Make the same assumptions about fast association rate constants as 9585556,
    # and use their measured values for dissociation rates in the absence of GEFs.
    # (association rates are in units of nM^-1 s^-1).
    def ras_binds_gtp_and_gdp(ras, k_gtp_diss, k_gdp_diss):
        kf = 1e-2
        bind_table([[                   GTP,               GDP],
                    [ras,  (kf, k_gtp_diss),  (kf, k_gdp_diss)]], 'gtp', 'p')

    # The data in Table 1 gives a value of 1.2e-5 for the dissociation rate with
    # GDP, whereas the text gives rates of 1e-5 and 2e-5 for GTP/GDP, respectively.
    ras_binds_gtp_and_gdp(HRAS, 1e-5, 2e-5)
    # The rate for KRAS/GDP association is given in Table 1 as 1.6e-5, but the
    # KRAS/GTP rate is not measured.
    ras_binds_gtp_and_gdp(KRAS, 8e-6, 1.6e-5)
    # The rate for NRAS/GDP association is given in Table 1 as 1.0e-5, but the
    # NRAS/GTP rate is not measured.
    ras_binds_gtp_and_gdp(KRAS, 5e-6, 1.0e-5)

Ras converts GTP to GDP
~~~~~~~~~~~~~~~~~~~~~~~

GTP hydrolysis by wild-type Ras is very slow in the absence of RasGAPs.

    [1569940]_: It has been reported that the in vitro GTPase activity of wild-type
    p21, which proceeds at a rate of 0.028 min^-1 at 37°C ([2502546]_), is
    accelerated 100- to 200-fold by GAP, as measured under nonsaturating
    conditions.

::

    # Convert 2.8e-2 min^-1 to units of s^-1
    wt_ras_hydrolysis_rate = 2.8e-2 * 60

    def ras_converts_gtp_to_gdp(ras):
        k = Parameter('k_{0}_gtpase'.format(ras.name), 1.)
        Rule('{0}_converts_GTP_GDP'.format(ras.name),
             ras(gtp=1) % GTP(p=1) >>
             ras(gtp=1) % GDP(p=1),
             k)

    ras_interactions(KRAS)


Ras regulation by GEFs
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