Chemical Reaction Models

Chemical Reaction Models

The biological models functionality is provided by DiffEqBiological.jl and helps the user to build discrete stochastic and differential equation based systems biological models. These tools allow one to define the models at a high level by specifying reactions and rate constants, and the creation of the actual problems is then handled by the modelling package.

The Reaction DSL - Basic

This section covers some of the basic syntax for building chemical reaction network models.

Basic syntax

The @reaction_network macro allows you to define reaction networks in a more scientific format. Its input is a set of chemical reactions and from them it generates a reaction network object which can be used as input to ODEProblem, SDEProblem and JumpProblem constructors.

The basic syntax is:

rn = @reaction_network begin
  2.0, X + Y --> XY               
  1.0, XY --> Z1 + Z2            
end

where each line corresponds to a chemical reaction. Each reaction consists of a reaction rate (the expression on the left hand side of ,), a set of substrates (the expression in-between , and -->), and a set of products (the expression on the right hand side of -->). The substrates and the products may contain one or more reactants, separated by +. The naming convention for these are the same as for normal variables in Julia.

The chemical reaction model is generated by the @reaction_network macro and stored in the rn variable (a normal variable, do not need to be called rn). The macro generates a differential equation model according to the law of mass action, in the above example the ODEs become:

\[\frac{d[X]}{dt} = -2 [X] [Y]\\ \frac{d[Y]}{dt} = -2 [X] [Y]\\ \frac{d[XY]}{dt} = 2 [X] [Y] - [XY]\\ \frac{d[Z1]}{dt}= [XY]\\ \frac{d[Z2]}{dt} = [XY]\]

Arrow variants

Several types of arrows are accepted by the DSL and works instead of -->. All of these works: >, , , , , , , , , . Backwards arrows can also be used to write the reaction in the opposite direction. Hence all of these three reactions are equivalent:

rn = @reaction_network begin
  1.0, X + Y --> XY               
  1.0, X + Y → XY      
  1.0, XY ← X + Y      
end

(note that due to technical reasons <-- cannot be used)

Using bi-directional arrows

Bi-directional arrows can be used to designate a reaction that goes two ways. These two models are equivalent:

rn = @reaction_network begin
  2.0, X + Y → XY             
  2.0, X + Y ← XY          
end
rn = @reaction_network begin
  2.0, X + Y ↔ XY               
end

If the reaction rate in the backwards and forwards directions are different they can be designated in the following way:

rn = @reaction_network begin
  (2.0,1.0) X + Y ↔ XY               
end

which is identical to

rn = @reaction_network begin
  2.0, X + Y → XY             
  1.0, X + Y ← XY          
end

Combining several reactions in one line

Several similar reactions can be combined in one line by providing a tuple of reaction rates and/or substrates and/or products. If several tuples are provided they much all be of identical length. These pairs of reaction networks are all identical:

rn1 = @reaction_network begin
  1.0, S → (P1,P2)               
end
rn2 = @reaction_network begin
  1.0, S → P1     
  1.0, S → P2 
end
rn1 = @reaction_network begin
  (1.0,2.0), (S1,S2) → P             
end
rn2 = @reaction_network begin
  1.0, S1 → P     
  2.0, S2 → P
end
rn1 = @reaction_network begin
  (1.0,2.0,3.0), (S1,S2,S3) → (P1,P2,P3)        
end
rn2 = @reaction_network begin
  1.0, S1 → P1
  2.0, S2 → P2   
  3.0, S3 → P3  
end

This can also be combined with bi-directional arrows in which case separate tuples can be provided for the backward and forward reaction rates separately. These reaction networks are identical

rn1 = @reaction_network begin
 (1.0,(1.0,2.0)), S ↔ (P1,P2)  
end
rn2 = @reaction_network begin
  1.0, S → P1
  1.0, S → P2
  1.0, P1 → S   
  2.0, P2 → S 
end

Production and Destruction and Stoichiometry

Sometimes reactants are produced/destroyed from/to nothing. This can be designated using either 0 or :

rn = @reaction_network begin
  2.0, 0 → X
  1.0, X → ∅
end

Sometimes several molecules of the same reactant is involved in a reaction, the stoichiometry of a reactant in a reaction can be set using a number. Here two species of X forms the dimer X2:

rn = @reaction_network begin
  1.0, 2X → X2
end

this corresponds to the differential equation:

\[\frac{d[X]}{dt} = -\frac{1}{2!} [X]^2\\ \frac{d[X2]}{dt} = \frac{1}{2!} [X]^2\]

Other numbers than 2 can be used and parenthesises can be used to use the same stoichiometry for several reactants:

rn = @reaction_network begin
  1.0, X + 2(Y + Z) → XY2Z2
end

Variable reaction rates

Reaction rates do not need to be constant, but can also depend on the current concentration of the various reactants (when e.g. one reactant activate the production of another one). E.g. this is a valid notation:

rn = @reaction_network begin
  X, Y → ∅
end

and will have Y degraded at rate

\[\frac{d[Y]}{dt} = -[X][Y]\]

Note that this is actually equivalent to the reaction

rn = @reaction_network begin
  1.0, X + Y → X
end

Most expressions and functions are valid reaction rates, e.g:

rn = @reaction_network begin
  2.0*X^2, 0 → X + Y
  gamma(Y)/5, X → ∅
  pi*X/Y, Y → ∅
end

please note that user defined functions cannot be used directly (see later section "User defined functions in reaction rates").

Defining parameters

Just as when defining normal differential equations using DifferentialEquations parameter values does not need to be set when the model is created. Components can be designated as parameters by declaring them at the end:

rn = @reaction_network begin
  p, ∅ → X
  d, X → ∅
end p d

Parameters can only exist in the reaction rates (where they can be mixed with reactants). All variables not declared at the end will be considered a reactant.

Pre-defined functions

The hill function and the michaelis-menten function, both which are common in biochemical reaction networks, are pre-defined and can be used as expected. These pairs of reactions are all equivalent:

rn1 = @reaction_network begin
  hill(X,v,K,n), ∅ → X
  v*X^n/(X^n+K^n), ∅ → X
end v K n
rn2 = @reaction_network begin
  mm(X,v,K), ∅ → X
  v*X/(X+K), ∅ → X
end v K

Model Simulation

Once created, a reaction network can be used as input to various problem types and the solved by DifferentialEquations.jl.

Deterministic simulations using ODEs

A reaction network can be used as input to a ODEProblem instead of a function, using probODE = ODEProblem(rn, args...; kwargs...) E.g. a model can be created and simulated using:

rn = @reaction_network begin
  p, ∅ → X
  d, X → ∅
end p d
p = [1.0,2.0]
u0 = [0.1]
tspan = (0.,1.)
prob = ODEProblem(rn,u0,tspan,p)
sol = solve(prob)

(if no parameters are given p does not need to be provided)

Stochastic simulations using SDEs

In a similar way a SDE can be created using probSDE = SDEProblem(rn, args...; kwargs...). In this case the chemical Langevin equations (as derived in Gillespie 2000) will be used to generate stochastic differential equations.

Stochastic simulations using discrete stochastic simulation algorithm

Instead of solving SDEs one can make stochastic simulations of the model using real copy numbers and a discrete stochastic simulation algorithm. This can be done using:

rn = @reaction_network begin
  p, ∅ → X
  d, X → ∅
end p d
p = [1.0,2.0]
u0 = [10]
tspan = (0.,1.)
discrete_prob = DiscreteProblem(u0,tspan,p)
jump_prob = JumpProblem(discrete_prob,Direct(),rn)
sol = solve(jump_prob,SSAStepper())

The Reaction DSL - Advanced

This section covers some of the more advanced syntax for building chemical reaction network models (still not very complicated!).

User defined functions in reaction rates

The reaction network DSL cannot "see" user defined functions. E.g. this is not correct syntax:

myHill(x) = 2.0*x^3/(x^3+1.5^3)
rn = @reaction_network begin
  myHill(X), ∅ → X
end

However, it is possible to define functions in such a way that the DSL can see them using the @reaction_func macro:

@reaction_func myHill(x) = 2.0*x^3/(x^3+1.5^3)
rn = @reaction_network begin
  myHill(X), ∅ → X
end

Defining a custom reaction network type

While the default type of a reaction network is reaction_network (which inherits from AbstractReactionNetwork) it is possible to define a custom type (which also will inherit from AbstractReactionNetwork) by adding the type name as a first argument to the @reaction_network macro:

rn = @reaction_network my_custom_type begin
  1.0, ∅ → X
end

Scaling noise in the chemical Langevin equations

When making stochastic simulations using SDEs it is possible to scale the amount of noise in the simulations by declaring a noise scaling parameter. This parameter is declared as a second argument to the @reaction_network macro (when scaling the noise one have to declare a custom type).

rn = @reaction_network my_custom_type ns begin
  1.0, ∅ → X
end

The noise scaling parameter is automatically added as a last argument to the parameter array (even if not declared at the end). E.g. this is correct syntax:

rn = @reaction_network my_custom_type ns begin
  1.0, ∅ → X
end
p = [0.1,]
u0 = [0.1]
tspan = (0.,1.)
prob = SDEProblem(rn,u0,tspan,p)
sol = solve(prob)

Here the amount of noise in the stochastic simulation will be reduced by a factor 10.

Ignoring mass kinetics

While one in almost all cases want the reaction rate to take the law of mass action into account, so the reaction

rn = @reaction_network my_custom_type ns begin
  k, X → ∅
end k

occur at the rate $d[X]/dt = -k[X]$, it is possible to ignore this by using any of the following non-filled arrows when declaring the reaction: , , , , , . This means that the reaction

rn = @reaction_network my_custom_type ns begin
  k, X ⇒ ∅
end k

will occur at rate $d[X]/dt = -k$ (which might become a problem since $[X]$ will be degraded at a constant rate even when very small or equal to 0.

The Reaction Network Object

The @reaction_network macro generate a reaction_network object which have several fields which can be accessed.

Examples

Example: Birth-Death Process

rs = @reaction_network begin
  c1, X --> 2X
  c2, X --> 0
  c3, 0 --> X
end c1 c2 c3
p = (2.0,1.0,0.5)
prob = DiscreteProblem([5], (0.0, 4.0), p)
jump_prob = JumpProblem(prob, Direct(), rs)
sol = solve(jump_prob, SSAStepper())

Example: Michaelis-Menten Enzyme Kinetics

rs = @reaction_network begin
  c1, S + E --> SE
  c2, SE --> S + E
  c3, SE --> P + E
end c1 c2 c3
p = (0.00166,0.0001,0.1)
# S = 301, E = 100, SE = 0, P = 0
prob = DiscreteProblem([301, 100, 0, 0], (0.0, 100.0), p)
jump_prob = JumpProblem(prob, Direct(), rs)
sol = solve(jump_prob, SSAStepper())