globals [ dA dB dC Kd KB rbound-A rbound-B time A-exp B-exp C-exp]
turtles-own [age bound partner]
breeds [rna a-protein b-protein c-protein]

to setup
ca
; setup variables
reset-counters
set rbound-A false ; set the bound state of the operon to false
set rbound-B false ; set the bound state of the operon to false
set dA 10 ; rate of protein A
set dB 10 ; rate of protein B
set dC 10 ; rate of protein C
set Kd 4 ; dissociation coefficient
set KB 100 ; binding coefficient


      ; create binding sites  
      ; red - A
      ask patches with [(pxcor = -13) and (pycor = 0)] [ set pcolor red set plabel "A" ]
      ; create "gene"
      ask patches with [(pxcor > -13) and (pxcor <= -5) and (pycor = 0)] [ set pcolor white ]

      ; blue - B
      ask patches with [(pxcor = -6) and (pycor = 0)] [ set pcolor blue set plabel "B" ]
      ; create "gene"
      ask patches with [(pxcor > -6) and (pxcor <= 0) and (pycor = 0)] [ set pcolor white ]
      
     ; blue - C
      ask patches with [(pxcor = 1) and (pycor = 0)] [ set pcolor gray set plabel "P" ]
      ask patches with [(pxcor = 2) and (pycor = 0)] [ set pcolor gray set plabel "P" ]
      ask patches with [(pxcor = 3) and (pycor = 0)] [ set pcolor green set plabel "C" ]
      ; create "gene"
      ask patches with [(pxcor > 3) and (pxcor <= 10) and (pycor = 0)] [ set pcolor white ]

      
      ; create ribosomes
      ask patches with [ ((pxcor < -12) or (pxcor > 13)) or ((pycor < -3) or (pycor > 5))] [ if random 10 = 1 [set pcolor cyan] ]
  plot-history
  plot-levels               
end

to go 
  set time time + 1
; do gene transcription
ask patches [

  if (plabel = "A") [
    if (gene-A = true and random 100 < dA ) [
      sprout 1 [
        set A-exp A-exp + 1
        set breed rna
        set partner nobody
        set shape "rna"
        set color red
        set bound false
        set age random 30
        set heading random 360
        fd 2
      ]
    ]
  ]
  
  if (plabel = "B") [
    if (gene-B = true and random 100 < dB) [
      sprout 1 [
        set B-exp B-exp + 1
        set breed rna
        set partner nobody
        set shape "rna"
        set color blue
        set bound false
        set age random 30
        set heading random 360
        fd 2
      ]
    ]
  ]

;; this determines which gate the system emulates
if (plabel = "C" ) [
  if (condition = "3" ) [if (not (rbound-A = true and rbound-B = true) ) [ express-c] ]
  if (condition = "4" ) [if (rbound-A = false and rbound-B = false) [ express-c]]
  if (condition = "1" ) [if (rbound-A = true and rbound-B = true) [ express-c]]
  if (condition = "2" ) [if (rbound-A = true or rbound-B = true) [ express-c]]
  if (condition = "5" ) [if ((rbound-A = true or rbound-B = true) and not (rbound-A = true and rbound-B = true)) [ express-c]]
]
]

; this was a bit tricky to get the order of events right
ask a-protein [
    without-interruption [bind-site-a]]
    ask b-protein [
    without-interruption [bind-site-b]]
ask turtles 
    [wander ;; both rnas and proteins check to see if they bind and otherwise move around
     grow-old] ;; both also are recycled by the cell machinery after a while.
plot-history
plot-levels
end

to express-c

  if ( random 100 < dC ) [
     sprout 1 [
       set C-exp C-exp + 1
       set breed rna
       set partner nobody
       set shape "rna"
       set color green
       set bound false
       set age random 30
       set heading random 360
       fd 2
     ]
   ]
 
end
 
; bind repressor to lacZ operon
to bind-site-a
  if (rbound-A = false and partner = nobody)
  [if (random 100 < Kb and breed = a-protein) [
    set bound true 
    set rbound-A true 
    setxy 1 0  
    set heading 180]]
end

to bind-site-b
  if (rbound-B = false and partner = nobody)
  [if (random 100 < Kb and breed = b-protein) [
    set bound true 
    set rbound-B true 
    setxy 2 0  
    set heading 180]]
end

; unbind repressor from lacZ operon
to unbind-site
  if ((random 100 < Kd) or (partner != nobody)) [
    ifelse (color = red) [set rbound-A false] [set rbound-B false] 
    set bound false  
    setxy random screen-size-x random screen-size-y
]
end

; have RNAs, proteins, and inducers move around the environment
to wander
  if (pcolor = cyan and shape = "rna") [  
    ;; this is the ribosome translating
    hatch 1 [
ifelse (color = blue) [set breed b-protein ] [ifelse (color = green) [set breed c-protein ] [set breed a-protein ]]         
    set shape "repressor"
    set bound false
    set age 0
    set heading random 360
    ]
  ] 
  ifelse (bound = true) [without-interruption [unbind-site]] [rt random 90 - random 90 fd 1 ]
end

to grow-old ;; cells break down rnas and proteins after a while.  
   set age age + 1
   if (age > (40 + random 100))  [if (bound != true) [die] ]
end


to plot-levels ;; this creates creates the bar graph 
    set-current-plot "Protein Concentrations"
    clear-plot
    set-current-plot-pen "A"
    ppd
    plotxy 1 count turtles with [breed = a-protein] 
    set-current-plot-pen "B"
    ppd
    plotxy 2 count turtles with [breed = b-protein] 
    set-current-plot-pen "C"
    ppd
    plotxy 3 count turtles with [breed = c-protein] 
end

to plot-history ;; this creates the line graph
  set-current-plot "Concentration History"
    set-current-plot-pen "A"
  plot ( count turtles with [breed = a-protein]  )
    set-current-plot-pen "B"
  plot ( count turtles with [breed = b-protein]  )
    set-current-plot-pen "C"
  plot ( count turtles with [breed = c-protein]  )
end

to reset-counters
set A-exp 0
set B-exp 0
set C-exp 0
set time 0
end

; This model was created as part of the 2004 BioQUEST Curriculum Consortium
; Summer Workshop.  
;
; Copyright 2004 by Steven Brewer.  All rights reserved.
; This model was inspired by many of the sample Netlogo models and parts 
; were based on functions from the Enzyme Kinetics model.  (Wilensky, U. (2001).  
; NetLogo Enzyme Kinetics model. http://ccl.northwestern.edu/netlogo/models/EnzymeKinetics. 
; Center for Connected Learning and Computer-Based Modeling, Northwestern University, 
; Evanston, IL.) 
;
; Permission to use, modify or redistribute this model is hereby granted,
; provided that both of the following requirements are followed:
; a) this copyright notice is included.
; b) this model will not be redistributed for profit without permission
;    from the authors.
; Contact the authors for appropriate licenses for redistribution for
; profit.
;
; To refer to this model in academic publications, please use:
; Brewer, S.D. (2004).  Logical Promoter: Simulating Logical Gates Using
; a Model of Gene Expression.  http://bcrc.bio.umass.edu/netlogo/models/LogicalPromoter
; Biology Computer Resource Center
;
; In other publications, please use:
; Copyright 2004 by Steven Brewer.  All rights reserved.  See
; http://bcrc.bio.umass.edu/netlogo/models/LogicalPromoter
; for terms of use.
@#$#@#$#@
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@#$#@#$#@
WHAT IS IT?
-----------
This is a model that demonstrates possible ways that two genes could bind and influence expression of a third, either turning it off or on.  The conditions modelled here are not an exhaustive range of the possiblities available in biological systems, but each condition represents an important class of control mechanisms. 

HOW IT WORKS
------------
In this system, there are three genes: A, B and C.  Genes A and B produce transcription factors.  Gene C has two promoters that the transcription factors can bind to.  Depending on the settings of the system, these are either enhancers (turning on transcription of C) or silencers (turning off transcription of C).

HOW TO USE IT
-------------
Click "setup" to create the genes and ribosomes.  

Click "go" to start the model.

Switches allow the user to turn genes A and B on and off.

A pop-up menu allows the user to select which logical gate to emulate.

A plot shows levels of A, B, and C.


THINGS TO NOTICE
----------------
Even when C is turned off, you may notice it occasionally being transcribed.  Why might this be?  Are some gates "leakier" than others?  Why?  You can use the counters to put
the system in equilibrium and then reset the counters and experiment with which configurations are most effective.

THINGS TO TRY
-------------
For each gate, determine what role the promoter is playing in the system (enhancer or silencer).  

Consider constructing a "truth table" that lists possible states of "A", "B", and "C" under each condition to help disinguish among conditions that otherwise may appear to be identical.

EXTENDING THE MODEL
-------------------
To simplify this model, a number of factors have been de-paramaterized, including the rates of each gene (dA, dB, dC) and the coefficients of binding and dissociation (KB and Kd).  By adding sliders, you could extend this model and explore the behavior of the system with different values.  By changing these values you can try to decrease the leakiness of the system and increase the speed of the system turning on or off.

CREDITS AND REFERENCES
----------------------
This model was created as part of the 2004 BioQUEST Curriculum Consortium
Summer Workshop.  

Copyright 2004 by Steven Brewer.  All rights reserved.

This model was inspired by many of the sample Netlogo models and parts were based on functions from the Enzyme Kinetics model.  (Wilensky, U. (2001).  NetLogo Enzyme Kinetics model. http://ccl.northwestern.edu/netlogo/models/EnzymeKinetics. Center for Connected Learning and Computer-Based Modeling, Northwestern University, Evanston, IL.)  
Permission to use, modify or redistribute this model is hereby granted,
provided that both of the following requirements are followed:
a) this copyright notice is included.
b) this model will not be redistributed for profit without permission
   from the authors.
Contact the authors for appropriate licenses for redistribution for
profit.

To refer to this model in academic publications, please use:
Brewer, S.D. (2004).  Logical Promoter: Simulating Logical Gates Using
a Model of Gene Expression.  http://bcrc.bio.umass.edu/netlogo/models/LogicalPromoter
Biology Computer Resource Center

In other publications, please use:
Copyright 2004 by Steven Brewer.  All rights reserved.  See
http://bcrc.bio.umass.edu/netlogo/models/LogicalPromoter
for terms of use.
@#$#@#$#@
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box
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inducer
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@#$#@#$#@
NetLogo 2.0.1
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