Fifth q-bio Summer School: Cell Signaling

This series of lectures will be focused on modeling cell signaling. We will begin with an overview of the inherent features of cell signaling systems, including multisite phosphorylation, ubiquitination and regulated recruitment (co-localization of enzymes and substrates). We will then discuss how these features complicate efforts to develop predictive mechanistic models of cell signaling systems and possible solutions, in particular the rule-based modeling approach. We will cover methods for simulating a model, visualizing and annotating a model, and fitting procedures. To cover the latter topic, we will also discuss the types of quantitative data available to support modeling efforts. We will make extensive use of software tools that are compatible with the BioNetGen language (BNGL) or the closely related Kappa language. An example of such a tool is BioNetGen (http://bionetgen.org).

Students will participate in a group project designed to introduce students to the essential steps in formulation and analysis of a rule-based model for a cell signaling system.

This lecture series in 2011 q-bio Summer School is organized by William S. Hlavacek. Please address all questions about this part of the summer school to its organizer.

Lecturers

• James R. Faeder, PhD, University of Pittsburgh School of Medicine
• Byron Goldstein, PhD, Los Alamos National Laboratory
• Ryan N. Gutenkunst, PhD, University of Arizona
• William S. Hlavacek, PhD, Los Alamos National Laboratory and University of New Mexico
• Edward C. Stites, MD, PhD, Translational Genomics Research Institute

Tutors

The experts listed below will be available to assist students during at least one of the lab exercises.

• Dipak Barua, Los Alamos National Laboratory
• Bin Hu, Los Alamos National Laboratory
• Jin Yang, Chinese Academy of Sciences and Max Planck Institute for Computational Biology, Shanghai

Lectures and Slides

All lectures will pertain to modeling of cell signaling systems, with an emphasis on the rule-based modeling approach. A schedule of lectures is provided below. Links to slides will appear below as lecture slides become available.

1. Overview of cell signaling and introduction to rule-based modeling, (Hlavacek), followed by afternoon lab on BNGL, July 25 (slides)
2. Methods for simulating rule-based models (Faeder), followed by afternoon lab on BioNetGen, August 1 (for slides and other materials, see below)
3. Software for rule-based modeling and applications (Faeder), followed by afternoon lab on RuleBender and NFsim, August 2 (for slides and other materials, see below)
4. Parameter estimation, sensitivity analysis and sloppiness (Gutenkunst), August 3 (slides)
5. Mechanistic rule-based models for understanding cancer biology (Stites), followed by afternoon lab, August 4
6. Parameters (Goldstein), followed by afternoon lab on parameter values and units, August 5 [Dr. Goldstein's plan is to talk about the three types of parameters that must be entered in a rule-based model of a signaling cascade: 1. Geometric factors such as the cytosolic volume, the surface area of the plasma membrane and the external volume associated with each cell; 2. The concentrations of the components of the model; and 3. The rate constants that describe the dynamics of the biochemistry that are encoded in the rules.]

Materials from Dr. Faeder:

• main slides for first and second lectures
• lectures notes about BNGL
• BioNetGen lab exercises

Topics

• Inherent features of cell signaling systems
• Combinatorial complexity
• Conventional modeling approaches
• The rule-based modeling approach
• Pitfalls of model specification
• Visualizing and annotating a rule-based model
• Generate-first simulation
• On-the-fly simulation
• Network-free simulation
• Software tools for simulation
• Fitting
• Sensitivity analysis
• Sloppiness

Labs

The following subjects will be covered:

• BioNetGen language (BNGL)
• Anatomy of a BioNetGen input file
• Using RuleBender, BioNetGen and NFsim
• Recommended units for rate constants
• Online resources useful for model building (e.g., UniProt, HPRD, and Phospho.ELM)
• Guidelines for model visualization and annotation - drawing an extended contact map and assembling a model guide

A link to a course that covers rule-based modeling at Pittsburgh is here.

Project

Two teams of students will work on a group project. The teams will be led by Sarah Olson and Karen Tkach.

Software

• RuleBender
• BioNetGen
• NFsim

Reading

Students are encouraged to read the following papers before the summer school.

• Scott JD, Pawson T (2009) Cell signaling in space and time: where proteins come together and when they're apart. Science 326, 1220-1224.
• Mayer BJ, Blinov ML, Loew LM (2009) Molecular machines or pleiomorphic ensembles: signaling complexes revisited. J. Biol. 8:81.

Course Credit

You may receive course credit from the University of New Mexico (3 credit hours) for participating in the Modeling Cell Signaling section of the 2011 q-bio Summer School. To learn more about the courses listed below, please contact Dr. Hlavacek (bhlavacek@tgen.org).

• Summer semester 2011, Undergraduate Problems (BIOL 499, Section 035, CRN:17299), Department of Biology, University of New Mexico
• Summer semester 2011, Research Problems (BIOL 551, Section 049, CRN:19876), Department of Biology, University of New Mexico