# Constraint Equations and Events

In many applications one has additional algebraic or differential equations for non-chemical species that can be coupled to a chemical reaction network model. Catalyst supports coupled differential and algebraic equations, and currently allows conversion of such coupled systems to ModelingToolkit ODESystems and NonlinearSystems. Likewise, one often needs events that can occur when a set condition is reached, such as providing a drug treatment at a specified time, or turning off production of cells once the population reaches a given level. Catalyst supports the event representation provided by ModelingToolkit, see here, allowing for both continuous and discrete events (though only the latter are supported when converting to JumpSystems currently).

In this tutorial we'll illustrate how to make use of constraint equations and events. Let's consider a model of a cell with volume $V(t)$ that grows at a rate $\lambda$. For now we'll assume the cell can grow indefinitely. We'll also keep track of one protein $P(t)$, which is produced at a rate proportional $V$ and can be degraded.

## Coupling ODE constraints via extending a system

There are several ways we can create our Catalyst model with the two reactions and ODE for $V(t)$. One approach is to use compositional modeling, create separate ReactionSystems and ODESystems with their respective components, and then extend the ReactionSystem with the ODESystem. Let's begin by creating these two systems:

using Catalyst, DifferentialEquations, Plots

# set the growth rate to 1.0
@parameters λ = 1.0

# set the initial volume to 1.0
@variables t V(t) = 1.0

# build the ODESystem for dV/dt
D = Differential(t)
eq = [D(V) ~ λ * V]
@named osys = ODESystem(eq, t)

# build the ReactionSystem with no protein initially
rn = @reaction_network begin
@species P(t) = 0.0
V, 0 --> P 1.0, P --> 0 end \begin{align*} \varnothing &\xrightleftharpoons[1.0]{V\left( t \right)} \mathrm{P} \end{align*} Notice, here we interpolated the variable V with V to ensure we use the same symbolic state variable in the rn as we used in building osys. See the doc section on interpolation of variables for more information.

We can now merge the two systems into one complete ReactionSystem model using ModelingToolkit.extend:

@named growing_cell = extend(osys, rn)
\begin{align*} \varnothing &\xrightleftharpoons[1.0]{V\left( t \right)} \mathrm{P} \\ \frac{\mathrm{d} V\left( t \right)}{\mathrm{d}t} &= V\left( t \right) \lambda \end{align*}

We see that the combined model now has both the reactions and ODEs as its equations. To solve and plot the model we proceed like normal

oprob = ODEProblem(growing_cell, [], (0.0, 1.0))
sol = solve(oprob, Tsit5())
plot(sol)

## Coupling ODE constraints via directly building a ReactionSystem

As an alternative to the previous approach, we could have constructed our ReactionSystem all at once by directly using the symbolic interface:

using Catalyst, DifferentialEquations, Plots

@parameters λ = 1.0
@variables t V(t) = 1.0
D = Differential(t)
eq = D(V) ~ λ * V
rx1 = @reaction $V, 0 --> P rx2 = @reaction 1.0, P --> 0 @named growing_cell = ReactionSystem([rx1, rx2, eq], t) setdefaults!(growing_cell, [:P => 0.0]) oprob = ODEProblem(growing_cell, [], (0.0, 1.0)) sol = solve(oprob, Tsit5()) plot(sol) ## Adding events Our current model is unrealistic in assuming the cell will grow exponentially forever. Let's modify it such that the cell divides in half every time its volume reaches a size of 2. We also assume we lose half of the protein upon division. Note, we will only keep track of one cell, and hence follow a specific lineage of the system. To do this we can create a continuous event using the ModelingToolkit symbolic event interface and attach it to our system. Please see the associated ModelingToolkit tutorial for more details on the types of events that can be represented symbolically. A lower-level approach for creating events via the DifferentialEquations.jl callback interface is illustrated in the Advanced Simulation Options tutorial. Let's first create our equations and states/species again using Catalyst, DifferentialEquations, Plots @parameters λ = 1.0 @variables t V(t) = 1.0 @species P(t) = 0.0 D = Differential(t) eq = D(V) ~ λ * V rx1 = @reaction$V, 0 --> $P rx2 = @reaction 1.0,$P --> 0
1.0, P --> ∅

Before creating our ReactionSystem we make the event.

# every 1.0 time unit we half the volume of the cell and the number of proteins
continuous_events = [V ~ 2.0] => [V ~ V/2, P ~ P/2]
Equation[V(t) ~ 2.0] => Equation[V(t) ~ (1//2)*V(t), P(t) ~ (1//2)*P(t)]

We can now create and simulate our model

@named rs = ReactionSystem([rx1, rx2, eq], t; continuous_events)

oprob = ODEProblem(rs, [], (0.0, 10.0))
sol = solve(oprob, Tsit5())
plot(sol; plotdensity = 1000)

We can also model discrete events. Similar to our example with continuous events, we start by creating reaction equations, parameters, variables, and states.

@parameters k_on switch_time k_off
@variables t
@species A(t) B(t)

rxs = [(@reaction k_on, A --> B), (@reaction k_off, B --> A)]
2-element Vector{Reaction{Any, Int64}}:
k_on, A --> B
k_off, B --> A

Now we add an event such that at time t (switch_time), k_on is set to zero.

discrete_events = (t == switch_time) => [k_on ~ 0.0]

u0 = [:A => 10.0, :B => 0.0]
tspan = (0.0, 4.0)
p = [k_on => 100.0, switch_time => 2.0, k_off => 10.0]
3-element Vector{Pair{Num, Float64}}:
k_on => 100.0
switch_time => 2.0
k_off => 10.0

Simulating our model,

@named osys = ReactionSystem(rxs, t, [A, B], [k_on, k_off, switch_time]; discrete_events)

oprob = ODEProblem(osys, u0, tspan, p)
sol = solve(oprob, Tsit5(); tstops = 2.0)
plot(sol)

Note that for discrete events we need to set a stop time, tstops, so that the ODE solver can step exactly to the specific time of our event. For a detailed discussion on how to directly use the lower-level but more flexible DifferentialEquations.jl event/callback interface, see the tutorial on event handling using callbacks.