/* reaction_mechanisms.mdl */

/* ACh-AChR interactions */
DEFINE_REACTION AChR {    /* reaction name is "AChR" */
/* Each state within a reaction mechanism implicitly defines a 
molecule that requires a name.  Here the AChR states are given 
names of "R0", "AR1", "AR2", "A2R3", and "A2R4" to correspond 
with the reaction mechanism shown in book Fig. 4.1.  Each state 
name is followed by a list of possible transition paths, one to 
each adjacent state.  Each path is enclosed in square brackets.  
The general syntax for each path is:
state_name[>adjacent_state_name{rate_constant}]
if the transition is a simple conformational change, or
state_name[>adjacent_state_name{rate_constant: 
?defined_molecule_name,polarity}]
if the transition includes an operation on another previously 
defined molecule.  The "?" symbol is a placeholder for one of 
several types of molecular operation, e.g., a "+" or "-" is used 
in this reaction to indicate ligand binding or unbinding, 
respectively.  For binding transitions, the second-order rate 
constant is given in liters/(mole second), while for all 
unimolecular transitions the first order rate constant is given 
in (1/second).
Since effector sites reside on mesh elements and the mesh 
elements have front and back faces, binding and unbinding 
operations have "polarity".  The effector site itself is 
considered to have a positive and negative "pole" (this 
terminology has no necessary relation to charge), and when an 
effector site is placed on a mesh element, the site's positive 
pole can be on either the element's front or back face (e.g., 
see muscle_membrane.mdl).  Then, in a reaction mechanism 
transition, polarity indicates whether the molecular event 
occurs on the effector site's positive or negative pole (or 
both).  Polarity is specified using several context-dependent 
keywords.  In this AChR reaction for effector sites on the 
muscle membrane mesh, ACh binding and unbinding both occur on 
the positive pole, which faces the synaptic cleft diffusion 
space. */
  R0[>AR1{1.35e8:+ACh,POSITIVE_POLE}][>AR2{1.35e8:+ACh,
POSITIVE_POLE}]    /* An effector site in the R0 state has two 
independent ACh binding sites on its positive pole.  Binding 
to one leads to the AR1 state; binding to the other leads to 
the AR2 state.  In this example the two sites happen to be 
statistically identical because the specified rate constants 
are identical. */
  AR1[>A2R3{1.35e8:+ACh,POSITIVE_POLE}][>R0{64286:-ACh,
POSITIVE_POLE}]    /* The AR1 state has one remaining ACh 
binding site, or can unbind ACh from the occupied site on its 
positive pole. */
  AR2[>A2R3{1.35e8:+ACh,POSITIVE_POLE}][>R0{64286:-ACh,
POSITIVE_POLE}]    /* The AR2 state has one remaining ACh 
binding site, or can unbind ACh from the occupied site on its 
positive pole. */
  A2R3[>A2R4{48750}][>AR1{64286:-ACh,POSITIVE_POLE}]
[>AR2{64286:-ACh,POSITIVE_POLE}]    /* The A2R3 state can 
undergo a conformational change to the A2R4 state, or can 
unbind an ACh molecule from either of the two occupied sites 
on its positive pole. */
  A2R4[>A2R3{1250}]    /* The A2R4 state can only undergo a 
conformational change back to the A2R3 state. */
  REFERENCE_STATE R0 {
    ACh NUMBER_BOUND = 0
  }    /* To track the number of bound and unbound molecules 
correctly, a baseline is established by picking one (any) 
state (R0 in this case) and listing the number of molecules 
bound to it. */
}

/* ACh-AChE interactions */
DEFINE_REACTION AChE {    /* State names correspond to the 
reaction mechanism shown in book Fig. 4.1. */
  E[>AE{2.0e8:+ACh,BOTH_POLES}]    /* Since AChE effector sites 
exist on the transparent basal lamina mesh within the synaptic 
cleft diffusion space (see basal_lamina.mdl and book Fig. 
4.4A), ACh binding is allowed on both the positive and 
negative poles. */
  AE[>AcE{112000:*Ch,EITHER_POLE}][>E{14000:-ACh,EITHER_POLE}]    
/* The transformation from AE to AcE produces (* operation) a 
diffusing Ch molecule from either the positive or negative 
pole, or the AE state can unbind ACh from either pole. */
  AcE[>E{18667:#ACh}][>AAcE{5.0e6:+ACh,BOTH_POLES}]    /* The 
transformation from AcE back to E irreversibly destroys (# 
operation) the ACh that had originally bound, or the AcE state 
can bind a second ACh molecule. */
  AAcE[>AcE{21429:-ACh,EITHER_POLE}][>AE{1867:#ACh}]    /* 
Unbinding or destruction can occur; destruction is slower than 
from the AcE state to simulate excess substrate inhibition. */
  REFERENCE_STATE E {
    ACh NUMBER_BOUND = 0
    Ch NUMBER_BOUND = 0
  }    /* Both ACh and Ch participate in the reaction and must be 
listed. */
}

/* Re-uptake of Ch produced by ACh-AChE reaction */
DEFINE_REACTION ChR {    /* State names must be unique within a 
reaction mechanism, but can be reused in different mechanisms 
(e.g., R0, AR1, and AR2 are used here and were also used 
previously in the AChR reaction). */
  R0[>AR1{1.0e8:+Ch,POSITIVE_POLE}]    /* Ch binds to the positive 
pole of reuptake effector sites on the nerve membrane mesh, 
i.e., from within the synaptic cleft (see nerve_membrane.mdl). 
*/
  AR1[>R0{1000:-Ch,POSITIVE_POLE}][>AR2{1.0e5}]    /* Ch can 
unbind to reenter the synaptic cleft, or the AR1 state can 
flip to an alternate conformation. */
  AR2[>R0{1000:-Ch,NEGATIVE_POLE}]    /* From the AR2 state, Ch 
can unbind from the negative pole to diffuse within the nerve, 
i.e., the Ch molecule has been transported across the nerve 
membrane mesh.  The effector site reenters the unbound R0 
state. */
  REFERENCE_STATE R0 {
    Ch NUMBER_BOUND = 0
  }    /* Only Ch can participate and is listed. */
}