Physics 434, 2012: Lectures 8, 9

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Back to Physics 434, 2012: Information Processing in Biology.

We are finishing the last topic to be covered in this block. Namely, we will introduce the master equation, the diffusion equation, and the Langevin equation. We will study their relation to each other and solve a few simple problems using each of the methods.

Brian Munsky has a great tutorial presentation discussing the master equation and the related stochastic modeling techniques.

Warmup questions

  1. No question for lecture 8.
  2. Lecture 9. Production of LacI is a process that takes many steps -- transcription, translation, each one of which is also a complex reaction. Is the master equation then a valid description of LacI production/degradation processes? More simply, suppose the production is a MIchaelis-Menten reaction. Does the master equation hold? If yes, when?

Main Lecture

  • Finishing off the discussion from Lecture 7.
  • We are now moving to the discussion of how transcription gets initiated in the lac operon. That is, how can one start transcription, when the lac repressor is bound to the DNA, and there's no LacY permease in the system, and hence no lactose to get the inhibitor off the DNA
  • LacI is produced at a certain constant rate randomly and gets diluted constantly as the cell volume increases. With the average number of LacI molecules around 10 per cell, what is the probability that, at any given moment of time, the cell, or a part of the cell near the LacI binding sites actually has no lac repressor molecules, and hence LacY and LacZ are transcribed?
    • We assume that molecules get created/diluted independently one at a time. The deterministic equation describing this is Failed to parse (MathML with SVG or PNG fallback (recommended for modern browsers and accessibility tools): Invalid response ("Math extension cannot connect to Restbase.") from server "https://wikimedia.org/api/rest_v1/":): {\displaystyle \frac{dn}{dt}=\alpha-rn} . We can write what's known as a master equation for the number of molecules, which would account for the stochasticity: Failed to parse (MathML with SVG or PNG fallback (recommended for modern browsers and accessibility tools): Invalid response ("Math extension cannot connect to Restbase.") from server "https://wikimedia.org/api/rest_v1/":): {\displaystyle n} : Failed to parse (MathML with SVG or PNG fallback (recommended for modern browsers and accessibility tools): Invalid response ("Math extension cannot connect to Restbase.") from server "https://wikimedia.org/api/rest_v1/":): {\displaystyle \frac{dP(n)}{dt}=-P(n)(rn+\alpha)+P(n+1)r(n+1)+P(n-1)\alpha} , and for Failed to parse (MathML with SVG or PNG fallback (recommended for modern browsers and accessibility tools): Invalid response ("Math extension cannot connect to Restbase.") from server "https://wikimedia.org/api/rest_v1/":): {\displaystyle n=0} this changes to Failed to parse (MathML with SVG or PNG fallback (recommended for modern browsers and accessibility tools): Invalid response ("Math extension cannot connect to Restbase.") from server "https://wikimedia.org/api/rest_v1/":): {\displaystyle \frac{dP(0)}{dt}=-P(0)\alpha+P(n+1)r(n+1)}
    • We can then ask what is the steady state solution of this equation. For this, we set Failed to parse (MathML with SVG or PNG fallback (recommended for modern browsers and accessibility tools): Invalid response ("Math extension cannot connect to Restbase.") from server "https://wikimedia.org/api/rest_v1/":): {\displaystyle d/dt=0} above.
    • We can verify explicitly that the Poisson equation Failed to parse (MathML with SVG or PNG fallback (recommended for modern browsers and accessibility tools): Invalid response ("Math extension cannot connect to Restbase.") from server "https://wikimedia.org/api/rest_v1/":): {\displaystyle P(n)=e^{-\alpha/r}\frac{(\alpha/r)^n}{n!}} is a solution of the above equation.
    • Hence probability of having very few (and some time zero) molecules of the lac repressor is not small -- and some cells will spontaneously initiate transcription. These cell will then grow faster than the cells that do not transcribe, making the whole colony look like it's metabolizing lactose. Great experimental work on this subject is Ozbudak et al., 2004.
  • We claim thus that both shutting off and initiating transcription are processes that are related to properties of random walks. This was pretty obvious for the shut-off. But it is not yet fully clear that the master equation above has much to do with random walks.
  • Imagine a particle moving as a continuous time, discrete space random walk on a 1-d lattice. What is the equation that describes the dynamics of the number of particles with time?
    • Let the left/right rates be Failed to parse (MathML with SVG or PNG fallback (recommended for modern browsers and accessibility tools): Invalid response ("Math extension cannot connect to Restbase.") from server "https://wikimedia.org/api/rest_v1/":): {\displaystyle \alpha_\pm} .
    • The master equation is Failed to parse (MathML with SVG or PNG fallback (recommended for modern browsers and accessibility tools): Invalid response ("Math extension cannot connect to Restbase.") from server "https://wikimedia.org/api/rest_v1/":): {\displaystyle \frac{dP(x)}{dt}=-P(x)(\alpha_+(x)+\alpha_-(x))+P(x+1)\alpha_-(x+1)+P(x-1)\alpha_+(x-1)} . This is very close to the master equation we wrote above. Seems like, indeed random walk has much to do with transcriptional initiation, but this is a biased walk in the number space, not in the physical space.
  • We now assume that the probability has a width of Failed to parse (MathML with SVG or PNG fallback (recommended for modern browsers and accessibility tools): Invalid response ("Math extension cannot connect to Restbase.") from server "https://wikimedia.org/api/rest_v1/":): {\displaystyle \sigma} which is much larger than the lattice step size Failed to parse (MathML with SVG or PNG fallback (recommended for modern browsers and accessibility tools): Invalid response ("Math extension cannot connect to Restbase.") from server "https://wikimedia.org/api/rest_v1/":): {\displaystyle \Delta x} . Then we can say that Failed to parse (MathML with SVG or PNG fallback (recommended for modern browsers and accessibility tools): Invalid response ("Math extension cannot connect to Restbase.") from server "https://wikimedia.org/api/rest_v1/":): {\displaystyle P(x)} changes little between nearby sites, and Failed to parse (MathML with SVG or PNG fallback (recommended for modern browsers and accessibility tools): Invalid response ("Math extension cannot connect to Restbase.") from server "https://wikimedia.org/api/rest_v1/":): {\displaystyle P(x\pm1)\approx P(x)+\frac{\partial P}{\partial x}(\pm 1) +\frac{1}{2}\frac{\partial^2 P}{\partial x^2}} .
    • We further assume that Failed to parse (MathML with SVG or PNG fallback (recommended for modern browsers and accessibility tools): Invalid response ("Math extension cannot connect to Restbase.") from server "https://wikimedia.org/api/rest_v1/":): {\displaystyle \alpha_\pm} are independent of Failed to parse (MathML with SVG or PNG fallback (recommended for modern browsers and accessibility tools): Invalid response ("Math extension cannot connect to Restbase.") from server "https://wikimedia.org/api/rest_v1/":): {\displaystyle x} .
    • We then get Failed to parse (MathML with SVG or PNG fallback (recommended for modern browsers and accessibility tools): Invalid response ("Math extension cannot connect to Restbase.") from server "https://wikimedia.org/api/rest_v1/":): {\displaystyle \frac{\partial P(x,t)}{\partial t}=(\alpha_+-\alpha_-)\frac{\partial P(x,t)}{\partial x}+(\alpha_++\alpha_-)\frac{\partial^2 P(x,t)}{\partial x^2}}
    • This is called the diffusion equation, often written as Failed to parse (MathML with SVG or PNG fallback (recommended for modern browsers and accessibility tools): Invalid response ("Math extension cannot connect to Restbase.") from server "https://wikimedia.org/api/rest_v1/":): {\displaystyle \frac{\partial P(x,t)}{\partial t}=v\frac{\partial P(x,t)}{\partial x}+D\frac{\partial^2 P(x,t)}{\partial x^2}}
    • An unbiased diffusion equation (also called diffusion without drift) would be Failed to parse (MathML with SVG or PNG fallback (recommended for modern browsers and accessibility tools): Invalid response ("Math extension cannot connect to Restbase.") from server "https://wikimedia.org/api/rest_v1/":): {\displaystyle \frac{\partial P(x,t)}{\partial t}=D\frac{\partial^2 P(x,t)}{\partial x^2}}
  • We can also interpret Failed to parse (MathML with SVG or PNG fallback (recommended for modern browsers and accessibility tools): Invalid response ("Math extension cannot connect to Restbase.") from server "https://wikimedia.org/api/rest_v1/":): {\displaystyle \rho=NP} , and then the equation becomes not the equation for diffusion of a probability of a single particle, but rather the equation for diffusion of the particle density. For linear problems and large molecular numbers, these descriptions are equivalent.
  • Let's solve this equation for a few special cases.
    • For the initial condition of Failed to parse (MathML with SVG or PNG fallback (recommended for modern browsers and accessibility tools): Invalid response ("Math extension cannot connect to Restbase.") from server "https://wikimedia.org/api/rest_v1/":): {\displaystyle \rho(x,0)=\delta(x)} (that is, all particles are at 0), the solution is given by a Gaussian distribution Failed to parse (MathML with SVG or PNG fallback (recommended for modern browsers and accessibility tools): Invalid response ("Math extension cannot connect to Restbase.") from server "https://wikimedia.org/api/rest_v1/":): {\displaystyle P(x,t)=\frac{1}{4\pi Dt}\exp\left[-\frac{x^2}{4Dt}\right]} . We can verify this explicitly in class.
    • If drift is present (verify this yourselves), then Failed to parse (MathML with SVG or PNG fallback (recommended for modern browsers and accessibility tools): Invalid response ("Math extension cannot connect to Restbase.") from server "https://wikimedia.org/api/rest_v1/":): {\displaystyle P(x,t)=\frac{1}{4\pi Dt}\exp\left[-\frac{(x-vt)^2}{4Dt}\right]} .
  • Does a similar diffusion description also exist for the repressor production model?
    • Assuming that Failed to parse (MathML with SVG or PNG fallback (recommended for modern browsers and accessibility tools): Invalid response ("Math extension cannot connect to Restbase.") from server "https://wikimedia.org/api/rest_v1/":): {\displaystyle \sigma\gg \Delta x} is now equivalent to saying that Failed to parse (MathML with SVG or PNG fallback (recommended for modern browsers and accessibility tools): Invalid response ("Math extension cannot connect to Restbase.") from server "https://wikimedia.org/api/rest_v1/":): {\displaystyle \sqrt{\langle n\rangle}\gg1} because the Poisson distribution has the width Failed to parse (MathML with SVG or PNG fallback (recommended for modern browsers and accessibility tools): Invalid response ("Math extension cannot connect to Restbase.") from server "https://wikimedia.org/api/rest_v1/":): {\displaystyle \sqrt{\langle n\rangle}} . This potentially could be a problematic assumption.
    • We then derive a diffusion-like equation, typically called the Fokker-Planck equation in this context, out of this master equation: Failed to parse (MathML with SVG or PNG fallback (recommended for modern browsers and accessibility tools): Invalid response ("Math extension cannot connect to Restbase.") from server "https://wikimedia.org/api/rest_v1/":): {\displaystyle \frac{\partial P}{\partial t}=\frac{\partial}{\partial n}\left\{(rn-\alpha)P(n) +\frac{1}{2}\frac{\partial }{\partial n}\left[(\alpha+rn)P(n)\right]\right\}} .
    • Notice that the derivatives structure is somewhat different from the diffusion equation above -- this is because now production and degradation depend on Failed to parse (MathML with SVG or PNG fallback (recommended for modern browsers and accessibility tools): Invalid response ("Math extension cannot connect to Restbase.") from server "https://wikimedia.org/api/rest_v1/":): {\displaystyle n} .
  • Let's again solve for the steady state. We set Failed to parse (MathML with SVG or PNG fallback (recommended for modern browsers and accessibility tools): Invalid response ("Math extension cannot connect to Restbase.") from server "https://wikimedia.org/api/rest_v1/":): {\displaystyle \partial/\partial t=0} .
    • Then Failed to parse (MathML with SVG or PNG fallback (recommended for modern browsers and accessibility tools): Invalid response ("Math extension cannot connect to Restbase.") from server "https://wikimedia.org/api/rest_v1/":): {\displaystyle (rn-\alpha)P(n) +\frac{1}{2}\frac{\partial }{\partial n}\left[(\alpha+rn)P(n)\right]=C} .
    • Near a peak of the distribution, Failed to parse (MathML with SVG or PNG fallback (recommended for modern browsers and accessibility tools): Invalid response ("Math extension cannot connect to Restbase.") from server "https://wikimedia.org/api/rest_v1/":): {\displaystyle n=\alpha/r} thus: Failed to parse (MathML with SVG or PNG fallback (recommended for modern browsers and accessibility tools): Invalid response ("Math extension cannot connect to Restbase.") from server "https://wikimedia.org/api/rest_v1/":): {\displaystyle (rn-\alpha)P(n) +\alpha\frac{\partial }{\partial n}P(n)=C} .
    • Failed to parse (MathML with SVG or PNG fallback (recommended for modern browsers and accessibility tools): Invalid response ("Math extension cannot connect to Restbase.") from server "https://wikimedia.org/api/rest_v1/":): {\displaystyle C=0} since Failed to parse (MathML with SVG or PNG fallback (recommended for modern browsers and accessibility tools): Invalid response ("Math extension cannot connect to Restbase.") from server "https://wikimedia.org/api/rest_v1/":): {\displaystyle P,\partial P\to0} at infinity. Thus Failed to parse (MathML with SVG or PNG fallback (recommended for modern browsers and accessibility tools): Invalid response ("Math extension cannot connect to Restbase.") from server "https://wikimedia.org/api/rest_v1/":): {\displaystyle n=\alpha/r} thus: Failed to parse (MathML with SVG or PNG fallback (recommended for modern browsers and accessibility tools): Invalid response ("Math extension cannot connect to Restbase.") from server "https://wikimedia.org/api/rest_v1/":): {\displaystyle (rn-\alpha)P(n) +\alpha\frac{\partial }{\partial n}P(n)=0} .
    • Then Failed to parse (MathML with SVG or PNG fallback (recommended for modern browsers and accessibility tools): Invalid response ("Math extension cannot connect to Restbase.") from server "https://wikimedia.org/api/rest_v1/":): {\displaystyle P(n)\sim \exp\left(-\frac{(n-\alpha/r)^2}{\alpha/r}\right)} . Notice that the Poisson approximates as a Gaussian in this regime.
  • This is a manifestation of the previous CLT result -- many distributions tend to Gaussians when Failed to parse (MathML with SVG or PNG fallback (recommended for modern browsers and accessibility tools): Invalid response ("Math extension cannot connect to Restbase.") from server "https://wikimedia.org/api/rest_v1/":): {\displaystyle n} is large.
  • Generally, Diffusion approximation is an approximation that replaces the underlying distributions by a combination of Gaussians. This is good for calculating the means, but has problem with the tails.
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