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How to model biochemical pathwaysan ODE approach

How do we model activation of an enzyme, e.g: CaMKII, PP2b by calcium?


We will first show a simple abstract example where a single molecule of Ca can bind and activate a substrate S Well mixed system explain.

T T [ S ] = S [ S Ca ] ; [ Ca ] = Ca [ S Ca ]

d[ S Ca] = k1[ S][Ca] k1[S Ca] dt = k1 (S T [ S Ca])(CaT [S Ca]) k1[ S Ca] = k1S T CaT ( k1( S T + CaT ) + k1 )[ S Ca] + k1[ S Ca]2
OOPS

Can assume: CaT>>ST, so that [Ca]=CaT This simplifies matters.

Using this we get: (show at home)

This is a first order linear ODE


Which has an exponential solution With fixed point: And time constant:

Cooperative activation of a substrate

correct

Assume:

Cooperative activation of a substrate

Assume: Under this assumption this is a linear equation for the vector S=(S, S1, S2)T where

The fixed point is:

Where: These types of results are often used to make the following claim: If the relationship has power greater than 1, the reaction is assumed to be cooperative.

This is usually done by fitting an equation of the form:


T n ( Ca ) * [ S 2] = Smax ; n T n ( kd ) + (Ca )

To experimental data This is called a hill equation, n is a hill coefficient.

An irreversible enzymatic reaction. Michaelis-Menten approach.

What is the F.P here? What is the equilibrium here?

=0

Pseudo steady state hypothesis (an approximation, not always a good one)

where Use: so where

This is the Michalis-Menten equation where Notes:

Lets create now a very simple, toy model for calcium dependent bidirectional synaptic plasticity. Assume synaptic weight is proportional to Ap.

Fixed point: Time constant:

Assume:
dA p = (Ca)((Ca) A p ) dt

Obtain:

Optional Homework ( I will drop the worst homework grade, can submit after final) a. Program the full Michaelis-Menten kinetics.

and show the dynamics at different values of the coefficients (ki), as well as initial [E] and [S] values. b. Show the dynamics of the reduced system, in the QSSA case. Compare to the full dynamics above, and look at the derivative, of the complex for different parameters. Are these dynamics consistent with the QSSA? Do the values of the coefficients influence if the assumptions are reasonable or not.

c. Code the calcium dependent plasticity model.

It is your job to make assumptions about K(Ca) and P(Ca). Find K(Ca) and P(Ca) that will generate and LTD/LTP model such that for Ca<0.3 we get no change, 0.3<Ca<0.8 we obtain LTD and for Ca>0.8 we get LTP. d. Compare the rate at which you converge to maximal LTD at Ca=0.5 and to maximal LTP at Ca=1.2. Is there a difference, if there is explain why.

Summary