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Prerequisites: Mathematics 1b required and MCB 54 or MCB 56 recommended. Also, see the note on page 7.
Sections: Matlab/Mathematica sections will be in Science Center 229; paper/discussion sections in Biolabs 1075.
Tue 9/18 *** Special evening Matlab/Mathematica section - Wed & Thu 6pm Science Center 229
Tue 9/25 Discussion, Biolabs 1075
Tue 10/2 Ferrell paper discussion, Biolabs 1075
Tue 10/9 Lewis paper discussion, Biolabs 1075
Tue 10/16 Discussion, Biolabs 1075
Tue 10/23 Hopfield paper discussion, Biolabs 1075
Tue 10/30 Barkai & Leibler paper discussion, Biolabs 1075
Tue 11/6 *** special Kappa section, location TBD
Tue 11/13 TBD
Tue 11/20 *** no section this week
Tue 11/27 TBD
Tue 12/4 TBD
Tue 12/11 TBD
Problem sets:
Handed out Due Handed out Due
Statement of purpose
We will pursue two aspects of intracellular dynamics (wherein we shall be concerned only with temporal – not
spatial – aspects).
One aspect emphasizes small network chunks – “motifs” – recognized as implementing distinct behaviors that are
useful in understanding biological systems. In this view, a motif is akin to what an engineer would call a “device”
– a dynamical system whose internal processes are decoupled from the states of the larger context in which the
system is embedded. This underscores the modular composition of motifs into larger networks.
The other aspect is concerned with large signaling networks characterized by vast numbers of possible states
brought about by numerous post-translational modifications and complex formation. In addition, these networks
appear oftentimes interwoven with other signaling systems through extensive sharing of components.
Both aspects call for different modeling approaches. Jeremy’s prior segment on systems of differential equations
will serve us well for the engineering perspective. We will carefully introduce a different approach apt to handle
large and complex systems that underlie cellular decision processes. A stochastic element is built into the latter
approach and provides a natural transition to Johan’s final segment on the in-depth treatment of stochastic
processes.
Binding equilibria:
Many events in biochemistry, molecular signaling, and the regulation of gene expression involve two steps: (1)
the reversible binding of substrates or ligands to an enzyme and (2) a subsequent irreversible reaction in which the
enzyme modifies the substrate(s). If the binding equilibrium is fast, it will determine the speed of the reaction.
Different types of binding equilibria lead to different functional forms for the reaction velocity, such as a
hyperbola (Michaelis-Menten), a shifted hyperbola (thresholds), or a sigmoid (Hill-function). Modelers often
simplify molecular systems by lumping together several “elementary” reactions into one “overall reaction”, whose
velocity as a function of substrate concentration is typically assumed to be one of the types above.
• Set up the kinetic rate equations of GK and understand what is the “input” (the ratio of enzyme A to
enzyme B) and what the “output” (the fraction of modified target T in steady-state)
• Discuss variations of the scheme throughout cellular processes (GEF/GAP, G proteins, etc.); point to
other schemes that we shall build from the GK loop (“in series” (multisite phosphorylation), “in parallel”
(MAP kinase cascades), and with feedback (Lisman switch)
• Discuss the analytical solution of GK and point out that the input/output relationship depends critically on
the amount of substrate T in the system. Discuss two very differently behaving regimes: both arms
unsaturated with T (hyperbolic dependence of output on input) and both arms saturated with T(“switch”-
like dependence of output on input)
• The case in which one arm is saturated but not the other leads to a behavior in which the output is
independent of the total amount of target substrate T (at steady-state):
o perfect adaptation of the system to concentration changes of T. This is one design principle of
chemotaxis.
o Clarify the difference between adaptation and a homeostat.
Step back and point out that chemotaxis of eukaryotic cells is executed in a different manner (“crawling” by
cytoskeletal rearrangements). Yet, despite differences in the parts list and the mode of locomotion, the eukaryotic
control circuitry seems to implement the same abstract principles as the bacterial case.
5
Lecture 12 (Thu 10/25):
Decorations of the GK loop
Expand the GK loop and transfer the lessons learned in Lecture 1 to steady-states of
• GK “in parallel”: multisite phosphorylation
• GK “in series”: cascade architectures
Adding a feedback to the versatile GK loop generates a simple bistable circuit (the Lisman model).
• Review and discuss the concept of bistability in the Lisman model (referring back to Jeremy’s segment).
Large networks
Transition: The changing nature of models (and modeling) from physics to biology
• The challenge of modeling large networks: Two axes of evil - state combinatorics and multiple scales
• The need of agent/rule-based approaches: A comparison to ordinary differential equations
• Modeling versus encoding
o The dangers of overfitting by using small network motifs and rate constants as a “programming
language”
This will be hands-on, interleaving the presentation of concepts with KappaFactory demos.
Multisite phosphorylation
Cascades
Contact maps
Causality
o At the level of rules: (low- and high-resolution) influence maps
o At the level of events: stories
The concept of a “story” and the notion of pathway
The superposition of stories and influence maps
EGF signaling
o Receptor networks
o Scaffolds
o Cascades: Ras-Raf-MEK-ERK and PI3K-PIP2/3-PDK1-AKT
o Feedback from ERK upstream and oscillations
7
Block 3 - Johan Paulsson
The first three lectures in this block will introduce the methods needed to model stochastic kinetics,
accompanied by simple toy models for chemical reactions. The following five lectures will then use the
techniques to introduce general principles for stochastic cell biology, and illustrate them with specific
examples. The last lecture summarizes the course and describes future challenges.
Note: Students are expected to know averages, variances, density functions, distribution functions,
probability distributions and the law of total probability. If you do not remember these parts, then please
consult an introduction to probability or statistics (for an online version, the Wikipedia entries work
fine).