Due Wednesday, October 11th, 2017

Submit Code online and handwritten derivations before lab at 4:40 PM

BME 260L HW 2: Mathematical Modeling and Metabolic Flux Analysis

Problem 1: 1D Stability of a Self-Regulating Gene Circuit

Consider the gene circuit above where a protein R regulates its own synthesis. The following set
of equations describes the full system.
[]
= []
+ []
[]
= [] []

Given that the mRNA dynamics happen on the order of second while the protein dynamics could
literally take hours, days, or months, we will assume that the mRNA is at quasi-steady state
reducing our system as follows:

[] =
( + [])
[]
= []
( + [])
We will parameterize the model as shown in the following equation:
[] 10
= 0.1[]
5 + []
1. Calculate the steady state of the system.
2. Create a rate balance plot showing the rate of generation, rate of decay, and net rate of
production of [R] on the interval [0, 15].
10
3. Analytically calculate the integral () = 5+[] 0.1[] , and plot the results.
4. Discuss the stability of the steady state.
5. Repeat the analysis for self-activating protein expression with cooperativity n = 2.
(Integration can be numeric)
[]2
= 0.1[]
5 + []2
Due Wednesday, October 11th, 2017
Submit Code online and handwritten derivations before lab at 4:40 PM

Problem 2: 2D Stability of a SIRS Epidemic

In epidemiology, the SIRS model (Susceptible-Infected-Recovered-Susceptible) describes the
temporal dynamics of the outbreak of a disease that the majority of the population can recover
from (without dying) and then become susceptible to again at some point in the future such as
the flu.

The model is described by the following nonlinear system of ODEs

= (, , ) = +


= (, , ) =


= (, , ) =


+ + =0++ =

1. Express the only non-trivial steady state of the system in terms of , , , . To
clarify, two other steady states exist (S = 0, I = 0, R = 0) and (S = P, I = 0, R = 0). Find
the only non-trivial steady state.
2. Let = 0.0005, = 0.1, = 0.001, = 500. Express the linearized system of
equations centered at the equilibrium in terms of the Jacobian Matrix.



[ ] = [ ]


[ ]
3. Write out the secular determinant of the Jacobian det( ) = 0. Then, use the eig( )
function in Matlab to find the eigenvalues and eigenvectors of the Jacobian Matrix.
Comment on the stability based on the eigenvalues.
4. Simulate the system over the time interval t = [0, 5000] with initial condition (S = 499, I
= 1, R = 0) using the parameters defined above. Plot the time course and a 3D phase
portrait using plot3( ).
Due Wednesday, October 11th, 2017
Submit Code online and handwritten derivations before lab at 4:40 PM

Problem 3: Sensitivity Analysis of Activated mRNA Transcription

mRNA temporal dynamics are typically described by the following equation.
[]
= []

Generally, the synthesis rate of mRNA (r) can be represented as
[]
= + 0
+ []
=
= ~
= ~
[] =
= (> 1 )
0 =
We can measure the strength of the activator in terms of the Fold Change in overall transcription
rate with respect to the leaky transcription rate.
[] 0 + (0 + )[]
= = 1+ =
0 0 + 0 [] 0 + 0 []
0 +
(1 + [] ) 1 + []
0 1
= =
[] 1 + 2 []
1 +

0 + 1 1
1 =
> = 2
0
1. For the general case n = n and for the specific case n = 1, derive the sensitivity for the
general case n = n and for the specific case n = 1, derive the sensitivity coefficient
ln() []
= = = 1,
ln([]) []

2. For 1 = 5, 2 = 1, = {1,2}, plot the fold change F (log scale) against the
concentration [A] (log scale) and the sensitivity curve S (normal axis) against the
concentration [A] (log scale).
3. Comment on the effects of cooperativity ( > 1) on the overall fold change and the
sensitivity. Why might cooperativity be beneficial for this system?
Due Wednesday, October 11th, 2017
Submit Code online and handwritten derivations before lab at 4:40 PM

Problem 4: Metabolic Flux Analysis

Consider the reaction network shown below (a simplified model of the glycolytic pathway).

Denote the species as s1 = G6P, s2 = F6P, s3 = TP, s4 = F2,6P2, s5 = AMP, s6 = ADP, and s7 =
ATP (where G6P is glucose-6-phosphate, F6P is fructose-6-phosphate, TP is the pool of triose
phosphates, and F2,6P2 is fructose-2,6-bisphosphate).

1. Determine the stoichiometry matrix N for the system. In this case, the stoichiometry
matrix has rank 6. (ie Multiple linearly dependent reactions exist)
2. Find the flux modes by finding the kernel of N (ie Nv = 0). In other words, find the
vectors that span the solution space of the equation. This can be accomplished by
Gaussian elimination (make a big excel spreadsheet) or by using the null( ) function in
Matlab. (Hint: There are 3 flux modes, but your solution and Matlabs might be different
linear combinations of each others).
3. Find the Conservation Laws by finding the kernel of NT (ie NT). The same approach can
be used as in the problem above but make sure to transpose your stoichiometry matrix.
(Hint: There is 1 conservation law).