Modeling and Manipulating Biomolecular Interactions

This half of the course is taught by Prof. Ernest Fraenkel. This section contains lecture notes, reading material, and suggested study problems. There is also an associated protein design project.

Overview

Diverse problems ranging from fundamental questions of molecular biology to drug development can be analyzed in terms of the interactions between specific biomolecules, including protein-DNA and kinase-substrate interactions. Techniques for modifying these interactions are an essential part of the biological engineer’s toolkit. This section of 20.320 will focus on methods for modeling and manipulating biomolecular interactions. By the end of this unit, you will know how to analyze biological networks and to re-engineer protein-protein and protein-drug complexes to make more potent biological agents.

Lecture Notes

These are Prof. Ernest Fraenkel’s lecture notes.

TOPICS
Introduction: Modeling and Manipulating Biomolecular Interactions (PDF)
Protein Structure and Energetics (PDF)
Interaction Specificity (PDF - 1.6MB)
Molecular Design Part 1 (PDF - 1.1MB)
Modeling Disease (PDF)
Protein Structure Prediction (PDF)
Network Modeling (PDF)

Teaching assistants Daniel Martin-Alarcon and Allison Claas took these lecture notes during class.

LEC #	TOPICS
12	Predictive models of biology, genome editing, sensors, light-activated proteins, new enzymes, electrostatics (PDF - 1.4MB)
13	Hydrogen bonding, the hydrophobic effect, how we represent proteins (PDF - 2.4MB)
14	Paralogues and orthologues, protein therapeutics (PDF) (These lecture notes are incomplete.)
15	Specificity (PDF)
16	The metropolis algorithm (PDF)
17	Gradient descent, molecular dynamics, ΔΔG for small molecules, pharma priorities (PDF - 1.8MB)
18	Drug development case study: Imatinib (PDF)
20	Guest lecture by Rebecca L. Carrier: Impact of drug delivery of effectiveness (PDF) Courtesy of Rebecca L. Carrier. Used with permission.
21	Protein folding: thermodynamics (PDF - 1.9MB)
22	Kinetics of folding, predicting protein structure (PDF - 2.2MB)
23	Structure from sequence (PDF - 1.3MB)
24	Kinases, graph theory, experimental and computational techniques (PDF - 1.3MB)

Reading Material (Optional)

Scheeff, Eric D., and J. Lynn Fink. “Fundamentals of Protein Structure.” In Structural Bioinformatics. Edited by Philip E. Bourne, and Helge Weissig. Wiley-Liss, 2003, pp. 15–39. ISBN: 9780471201991. [Preview with Google Books]

Grinstead, Charles M., and J. Laurie Snell, eds. Introduction to Probability. American Mathematical Society, 1997. ISBN: 9780821807491. [Preview with Google Books]

Woolf, Peter, Burge Christopher, et al. Statistics and Probability Primer for Computational Biologists (PDF). 2004. (Courtesy of the authors. Used with permission.)

This design project accompanies the Modeling and Manipulating Biomolecular Interactions section.

Bromodomains are protein domains that specifically recognize acetylated lysines. Given the prevalence of acetylated lysines in complexes involved in chromatin-remodeling, DNA damage and cell-cycle control, bromodomains play a key role in a variety of cellular processes. In this project, we will use computational tools to mutate an existing bromodomain such that it has a higher affinity for a novel acetylated peptide compared to its actual biological peptide substrate. The project will consist of four stages:

Use PyMOL and PyRosetta to visualize the original bromodomain-ligand complex (If you are a student or teacher, you may be able to register for an educational-use-only PyMOL license.)
Outline the thermodynamic cycle required to calculate the difference in the binding energy between a mutant bromodomain and the novel peptide and a mutant bromodomain and the original peptide.
Utilize PyRosetta to replace the original peptide ligand with the new peptide ligand and optimize the resulting interface without mutating the bromodomain.
Utilize PyRosetta to optimize the interface of the new complex by mutating the bromodomain. Compute the change in binding energy / affinity mentioned above using thermodynamic cycles and the energetics obtained from PyRosetta.

Note: Appendix A is a basic PyMOL primer. Appendix B is a basic PyRosetta primer.

PROJECT HANDOUTS	SUPPORTING FILES
Protein Design Project - Parts 1 and 2 and Appendices A and B (PDF - 1.6MB)	2DVQ_project.pdb (PDB)
Protein Design Project - Part 3 and Appendices A and B (PDF - 2.2MB)	peptide_assignments.xls (XLS)
Protein Design Project - Part 4 and Appendices A and B (PDF - 2.2MB)

Problems (Optional)

These optional problems, along with others and solutions, are available in the Study Materials section.

While these problems are not turned in for grading, they will greatly help you prepare for the exams. Success in this class depends on keeping up to date on the material and practicing working through problems. These are great problems to work through and come to office hours with questions for, even though answer keys are available with the problems in the portfolio with previous years’ problems.

The additional reference problems tend to be more coding-based and will help with additional practice to help with the design project.

TOPICS	HIGHLY SUGGESTED PROBLEMS	ADDITIONAL REFERENCE PROBLEMS
Protein Structure, Energetics	2009, Problem Set 1, #3 2010, Problem Set 6, #3 2011, Problem Set 1, #3 2011, Problem Set 2, #1	2009, Problem Set 1, #1 2009, Problem Set 2, #1 2010, Problem Set 6, #1, 2 2011, Problem Set 1, #2 2011, Problem Set 2, #3
Specificity, Molecular Design	2011, Problem Set 2, #1 2011, Problem Set 3, #2	2011, Problem Set 3, #3

TOPICS

HIGHLY SUGGESTED PROBLEMS

ADDITIONAL REFERENCE PROBLEMS

Protein Structure, Energetics

2009, Problem Set 1, #3

2010, Problem Set 6, #3

2011, Problem Set 1, #3

2011, Problem Set 2, #1

2009, Problem Set 1, #1

2009, Problem Set 2, #1

2010, Problem Set 6, #1, 2

2011, Problem Set 1, #2