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Cathepsin Enzyme Reactions

using AlgebraicPetri
using Catlab.Programs
using Catlab.Graphics
using Catlab.WiringDiagrams
using Catlab.CategoricalAlgebra

using DifferentialEquations
using Plots

display_uwd(ex, prog="neato") = to_graphviz(ex, box_labels=:name, junction_labels=:variable, graph_attrs=Dict(:overlap => "false"), prog=prog)
ode(x, t) = ODEProblem(vectorfield(x), concentrations(x), t, rates(x));

Define objects and initial conditions

ob(x) = codom(Open([first(x)], LabelledReactionNet{Number,Int}(x), [first(x)])).ob;
K = :K=>33000;
S = :S=>33000;
L = :L=>33000;
Kinact = :Kinact=>0;
Sinact = :Sinact=>0;
Linact = :Linact=>0;
E = :E=>700000;
G = :G=>1300000;

Helper functions for generating primitive Petri net operations

inact(in,on::Number) = begin
  inact = Symbol(first(in), :inact)
  Open(LabelledReactionNet{Number,Int}(unique((in, inact=>0)), ((Symbol(:inact_,first(in)),on),first(in)=>inact)))
end;

bind(in1, in2, on::Number, off::Number) = begin
  out = Symbol(first(in1),first(in2))
  Open(LabelledReactionNet{Number,Int}(unique((in1, in2,out=>0)), ((Symbol(:bind_,first(in1),first(in2)),on),(first(in1),first(in2))=>out),
                                                           ((Symbol(:unbind_,out),off),out=>(first(in1),first(in2)))))
end;

deg(prod1,prod2,on::Number) = begin
  in = Symbol(first(prod1),first(prod2))
  prod2str = String(first(prod2))
  degprod2 = Symbol(endswith(prod2str, "inact") ? first(prod2str) : prod2str, :deg)
  Open(LabelledReactionNet{Number,Int}(unique((in=>0, prod1,degprod2=>0)), ((Symbol(:deg_,in),on),in=>(first(prod1),degprod2))));
end;

Cathepsin X reacting with itself

catX = @relation (X, Xinact, Xdeg) where (X, Xinact, Xdeg, XX, XXinact) begin
  inactX(X, Xinact)
  bindXX(X, XX)
  degXX(XX, X, Xdeg)
  bindXXinact(X, Xinact, XXinact)
  degXXinact(XXinact, X, Xdeg)
end
display_uwd(catX)
G n1 inactX n9 X n1--n9 n10 Xinact n1--n10 n2 bindXX n2--n9 n12 XX n2--n12 n3 degXX n3--n9 n11 Xdeg n3--n11 n3--n12 n4 bindXXinact n4--n9 n4--n10 n13 XXinact n4--n13 n5 degXXinact n5--n9 n5--n11 n5--n13 n6--n9 n7--n10 n8--n11

Cathepsin X reacting with Substrate Y

catXsubY = @relation (X, Xinact, Xdeg, Y, Ydeg) where (X, Xinact, Xdeg, Y, XY, Ydeg) begin
  bindXY(X, Y, XY)
  degXY(XY, X, Ydeg)
end
display_uwd(catXsubY)
G n1 bindXY n8 X n1--n8 n11 Y n1--n11 n12 XY n1--n12 n2 degXY n2--n8 n2--n12 n13 Ydeg n2--n13 n3--n8 n9 Xinact n4--n9 n10 Xdeg n5--n10 n6--n11 n7--n13

Cathepsin X reacting with Cathepsin Y

catXY = @relation (X, Xinact, Xdeg, Y, Yinact, Ydeg) where (X, Xinact, Xdeg, Y, Yinact, Ydeg, XY, XYinact) begin
  bindXY(X, Y, XY)
  degXY(XY, X, Ydeg)
  bindXYinact(X, Yinact, XYinact)
  degXYinact(XYinact, X, Ydeg)
end
display_uwd(catXY)
G n1 bindXY n11 X n1--n11 n14 Y n1--n14 n17 XY n1--n17 n2 degXY n2--n11 n16 Ydeg n2--n16 n2--n17 n3 bindXYinact n3--n11 n15 Yinact n3--n15 n18 XYinact n3--n18 n4 degXYinact n4--n11 n4--n16 n4--n18 n5--n11 n12 Xinact n6--n12 n13 Xdeg n7--n13 n8--n14 n9--n15 n10--n16

Define all enzyme reactions

rxns = Dict(
  :K => [inact(K, 7.494e-10)
         bind(K, K, 7.814e-4, 3.867e-3)
         deg(K, K, 2.265e-1)
         bind(K, Kinact, 7.814e-4, 3.867e-3)
         deg(K, Kinact, 2.265e-1)],
  :S => [inact(S, 7.494e-10)
         bind(S, S, 7.814e-4, 3.867e-3)
         deg(S, S, 2.265e-1)
         bind(S, Sinact, 7.814e-4, 3.867e-3)
         deg(S, Sinact, 2.265e-1)],
  :L => [inact(L, 7.494e-10)
         bind(L, L, 7.814e-4, 3.867e-3)
         deg(L, L, 2.265e-1)
         bind(L, Linact, 7.814e-4, 3.867e-3)
         deg(L, Linact, 2.265e-1)],
  :KE => [bind(K, E, 9.668e-6, 1e-2)
          deg(K, E, 1.728e0)],
  :KG => [bind(K, G, 2.764e-6, 8.78e-1)
          deg(K, G, 1.502)],
  :SE => [bind(S, E, 4.197e-7, 1.06e-3)
          deg(S, E, 1.384e4)],
  :SG => [bind(S, G, 5.152e-8, 3.894e-3)
          deg(S, G, 8.755e-1)],
  :LE => [bind(L, E, 1.977e-8, 1e-2)
          deg(L, E, 1.066e2)],
  :LG => [bind(L, G, 3.394e-8, 2.365e1)
          deg(L, G, 4.352)],
  :KS => [bind(K, S, 8.822e-4, 4.114e5)
          deg(K, S, 9e-10)
          bind(K, Sinact, 8.822e-4, 4.114e5)
          deg(K, Sinact, 9e-10)],
  :KL => [bind(K, L, 1.756e-4, 3.729e4)
          deg(K, L, 6.505e6)
          bind(K, Linact, 1.756e-4, 3.729e4)
          deg(K, Linact, 6.505e6)],
  :SK => [bind(S, K, 8.822e-4, 4.114e5)
          deg(S, K, 9e-10)
          bind(S, Kinact, 8.822e-4, 4.114e5)
          deg(S, Kinact, 9e-10)],
  :SL => [bind(S, L, 1e-3, 5e2)
          deg(S, L, 1e-7)
          bind(S, Linact, 1e-3, 5e2)
          deg(S, Linact, 1e-7)],
  :LK => [bind(L, K, 1e-3, 4.118e3)
          deg(L, K, 3.234e1)
          bind(L, Kinact, 1e-3, 4.118e3)
          deg(L, Kinact, 3.234e1)],
  :LS => [bind(L, S, 1.056e-12, 5e2)
          deg(L, S, 5e-1)
          bind(L, Sinact, 1.056e-12, 5e2)
          deg(L, Sinact, 5e-1)]
);

Helper functions to generate oapply calls

cat(cat) = begin
  catsym = first(cat)
  out = oapply(catX, Dict([:inactX, :bindXX, :degXX, :bindXXinact, :degXXinact] .=> rxns[catsym]), Dict(
    :X=>ob(cat),
    :Xinact=>ob(Symbol(catsym,:inact)=>0),
    :Xdeg=>ob(Symbol(catsym,:deg)=>0),
    :XX=>ob(Symbol(catsym,catsym)=>0),
    :XXinact=>ob(Symbol(catsym,catsym,:inact)=>0)))
  bundle_legs(out, [[1,2,3]])
end

cat_sub(cat1, sub) = begin
  catsym = first(cat1)
  subsym = first(sub)
  catsub = Symbol(catsym, subsym)
  out = oapply(catXsubY, Dict([:bindXY, :degXY] .=> rxns[catsub]), Dict(
    :X=>ob(cat1),
    :Xinact=>ob(Symbol(catsym,:inact)=>0),
    :Xdeg=>ob(Symbol(catsym,:deg)=>0),
    :Y=>ob(sub),
    :XY=>ob(Symbol(catsym,subsym)=>0),
    :Ydeg=>ob(Symbol(subsym,:deg)=>0)))
  bundle_legs(out, [[1,2,3], [4,5]])
end


cat_cat(cat1, cat2) = begin
  cat1sym = first(cat1)
  cat2sym = first(cat2)
  catcat = Symbol(cat1sym, cat2sym)
  out = oapply(catXY, Dict([:bindXY, :degXY, :bindXYinact, :degXYinact] .=> rxns[catcat]), Dict(
    :X=>ob(cat1),
    :Xinact=>ob(Symbol(cat1sym,:inact)=>0),
    :Xdeg=>ob(Symbol(cat1sym,:deg)=>0),
    :Y=>ob(cat2),
    :Yinact=>ob(Symbol(cat2sym,:inact)=>0),
    :Ydeg=>ob(Symbol(cat2sym,:deg)=>0),
    :XY=>ob(catcat=>0),
    :XYinact=>ob(Symbol(catcat,:inact)=>0)))
  bundle_legs(out, [[1,2,3], [4,5,6]])
end

functor(x) = oapply(x, Dict(
  :catK=>cat(K),
  :catS=>cat(S),
  :catL=>cat(L),
  :catKcatS=>cat_cat(K,S),
  :catKcatL=>cat_cat(K,L),
  :catScatK=>cat_cat(S,K),
  :catScatL=>cat_cat(S,L),
  :catLcatK=>cat_cat(L,K),
  :catLcatS=>cat_cat(L,S),
  :catKsubE=>cat_sub(K,E),
  :catSsubE=>cat_sub(S,E),
  :catLsubE=>cat_sub(L,E),
  :catKsubG=>cat_sub(K,G),
  :catSsubG=>cat_sub(S,G),
  :catLsubG=>cat_sub(L,G)));

function enzyme_uwd(enzymes::Array{Symbol}, substrates::Array{Symbol})
  rel = RelationDiagram{Symbol}(0)

  chemicals = vcat(substrates, enzymes)

  subs = add_junctions!(rel, length(substrates), variable=substrates)
  enzs = add_junctions!(rel, length(enzymes), variable=enzymes)
  nsubs = length(subs)
  nenzs = length(enzs)

  catx = add_parts!(rel, :Box, nenzs, name=[Symbol("cat$i") for i in enzymes])
  add_parts!(rel, :Port, nenzs, junction=enzs, box=catx)

  for x in 1:nenzs
    for y in 1:nenzs
      if y != x
        catxy = add_part!(rel, :Box, name=Symbol("cat$(enzymes[x])cat$(enzymes[y])"))
        add_parts!(rel, :Port, 2, junction=[enzs[x], enzs[y]], box=catxy)
      end
    end
  end

  for x in 1:nenzs
    for y in 1:nsubs
      catxy = add_part!(rel, :Box, name=Symbol("cat$(enzymes[x])sub$(substrates[y])"))
      add_parts!(rel, :Port, 2, junction=[enzs[x], subs[y]], box=catxy)
    end
  end
  add_parts!(rel, :OuterPort, length(chemicals), outer_junction = vcat(subs, enzs))
  rel
end

enzyme_reaction(args...) = enzyme_uwd(args...) |> functor |> apex
enzyme_reaction (generic function with 1 method)

Manually Defining Models

KSE = @relation (K, S, E) begin
  catK(K)
  catS(S)
  catKcatS(K, S)
  catScatK(S, K)
  catKsubE(K, E)
  catSsubE(S, E)
end
display_uwd(KSE)
G n1 catK n10 K n1--n10 n2 catS n11 S n2--n11 n3 catKcatS n3--n10 n3--n11 n4 catScatK n4--n10 n4--n11 n5 catKsubE n5--n10 n12 E n5--n12 n6 catSsubE n6--n11 n6--n12 n7--n10 n8--n11 n9--n12

Defining Models using API

CatK, CatS, Elastin

KSE = enzyme_uwd([:K, :S], [:E])
display_uwd(KSE)
G n1 catK n11 K n1--n11 n2 catS n12 S n2--n12 n3 catKcatS n3--n11 n3--n12 n4 catScatK n4--n11 n4--n12 n5 catKsubE n10 E n5--n10 n5--n11 n6 catSsubE n6--n10 n6--n12 n7--n10 n8--n11 n9--n12 
KSE_petri = apex(functor(KSE))
ode_prob = ode(KSE_petri, (0.0, 120.0))
sol = solve(ode_prob)

plot(sol)
plot(sol, lw = 2, ylims = (0, 15000), xlims = (0, 30))

CatK, CatS, CatL, Elastin

KSLE = enzyme_reaction([:K, :S, :L], [:E])
ode_prob = ode(KSLE, (0.0,120.0))
sol = solve(ode_prob)
plot(sol, lw = 1, size = (1066, 600))
plot(sol, ylims = (0, 20000), xlims = (0, 30), lw = 2, size = (1066, 600))

CatK, CatS, CatL, Elastin, Gelatin

KSLEG = enzyme_reaction([:K, :S, :L], [:E, :G])
ode_prob = ode(KSLEG, (0.0,120.0))
sol = solve(ode_prob)
plot(sol, lw = 1, size = (1066, 600))
plot(sol, ylims = (0, 30000), xlims = (0, 50), lw = 2, size = (1066, 600))