Topics in Computational Molecular Biology

Computer Science 88/188
Spring, 2000

Tues, Thurs 2:00-3:50

Place: 213 Sudikoff

Professor Bruce Randall Donald

113 Sudikoff Lab, x6-3173

http://www.cs.dartmouth.edu/~brd/Teaching/Bio/2000

Overview

Schedule

Bibliography

Some Relevant WWW Links

How to give a good talk

Projects

Overview

"Strictly speaking, molecular biology is not a new discipline, but rather a new way of looking at organisms as reservoirs and transmitters of information. This new vision opened up possibilities of action and intervention that were revealed during the growth of genetic engineering."

- Michel Morange,
"A History of Molecular Biology," Harvard University Press (1998).

Our goal is to look at some algorithmic problems related to three-dimensional structures in chemistry and molecular biology, emphasizing the perspective of geometric algorithms. We hope to consider a variety of topics (guided by the interests of the participants), and to make the seminar interesting to people with as wide a range of backgrounds as possible. Some of the topics we may cover include: Protein and RNA-folding, Distance Geometry and Assignment for Protein NMR, DNA arrays, the Phase Problem in X-ray Crystallography, Rational Drug Design, Molecular Docking, identifying structural domains and motifs in proteins, and conformational search.

The CS-Bio seminar is open to graduate students, and advanced undergraduates with a background in both algorithms and systems (at least CS 25 and CS 23). A background in biology is useful but not required. Students should be interested in doing some outside reading in biochemistry and biophysics. Students will be required to present papers in the seminar, and to do a project. Non-CS students (e.g., in biology and chemistry) with an interest in computational issues are invited as well; please speak with me about your background first though.

If you took my previous CS-Bio seminar in 1998, I estimate that the papers we will read will have about 20% overlap. I plan for us to read a largely different corpus; for example, we may read several papers on structural genomics, and papers on mass spectrometry for functional genomics.

How to Give a Good Talk

If you are scheduled to give a talk, I've prepared a set of hints for giving a good talk that I encourage you to look over.

Projects

Students will be required to do a project. Pick something in the general area of computational molecular biology or algorithms for structural molecular biology you are interested in, and (a) implement it, (b) analyze it, (c) improve it, (d) extend it, or (e) apply it. A one-page written project proposal is due on May 9.

Final projects are due on the last day of class. You must

Turn in a written report, and
Make a web page about your project.

(1) and (2) can be the same document.
Email me the webpage for your report. E.g., "http://www.cs.dartmouth.edu/~hood/compbio/index.html".
Your final report can be in html or PostScript from LaTeX. If you want to use another format, ask me first.
I suggest your final report should contain many illustrative pictures and figures.
If you wrote code, I would like to see it. Please include the code with your writeup, and link to it from your webpage.

Recommended Textbooks

Here is a list of recommended textbooks.

Schedule and Readings

*Papers that are not available online (below) have been handed out on paper.

*RECOMB papers (Proceedings of the N^th Annual International Conference on Computational Molecular Biology (N=1,2,3,4)) are available online via the ACM Digital Library.

March 28
Welcome
Introduction to Computational Biology and Chemistry.
Administrivia.
Reading:
- Principles of Protein Structure
- Biology Hypertextbook
- Streyer, Ch. 1&2 and pp 62-68.
Do these tasks:
- Read about and download RasMol on your machine to be able to view and manipulate biopolymers.
- To read the papers, you will need to be able to download and print PostScript files and Adobe PDF files from the WWW. Please familiarize yourself with how to do this.
Discussion:
March 30
Presenting: Chris Bailey-Kellogg.
NMR Assignment and Structure
- Background Reading:
  - Cavanagh et al, chapter 8.
    - Reference: Protein NMR Spectroscopy : Principles and Practice by John Cavanagh, Arthur G., III Palmer, Wayne Fairbrother (Contributor), Nick Skelton (Contributor) Hardcover - 587 pages (April 1996) Academic Pr; ISBN: 0121644901
  - Refer to Wüthrich as needed for reference
    - Reference: NMR of Proteins and Nucleic Acids by Kurt Wuthrich Hardcover - 320 pages (September 1986) John Wiley & Sons; ISBN: 0471828939
  - Online Tutorials, Notes, and References on NMR
April 4
Protein Design
Presenting: Bruce Donald.
Abstract
Reading: De Novo Protein Design: Fully Automated Sequence Selection [PDF]
Science (1997) October 3; 278 (5335):82 B. I. Dahiyat and S. L. Mayo.
- Help with PDF files.
- Introductory Reading:
  - Protein Geometry and Modelling [Gzipped PostScript]
- Background Reading:
  - Clinical significance of Protein Science [PDF]
  - Transcription factors (DNA-binding Proteins) for control of gene expression
    - A more detailed paper on transcription factors [PDF]
April 6 and April 11
Donald Lab away at RECOMB'2000 Bruce and Chris at RECOMB
April 13
Presenting: Tim Danford.
Gene chips

Reading:
- Clustering Gene Expression Patterns, A. Ben-Dor, Z. Yakhini (RECOMB'99)
- Algorithms for Choosing Differential Gene Expression Experiments, R. M. Karp, R. Stoughton, K. Y. Yeung (RECOMB'99)
- An Algorithm for Clustinering cDNAs for Gene Expression Analysis, E. Hartuv, A. Schmitt, J. Lange, S. Meirer-Ewert, H. Lehrach, R. Shamir (RECOMB'99)
April 18
Presenting: Cliff Stein.
Protein Threading
Reading:
- "Global Optimum Protein Threading with Gapped Alignment and Empirical Pair Potentials," Lathrop, R.H. and Smith, T.F., J. Mol. Biol. (cover article), 255:641-665, Feb., 1996.
- Cover Picture
April 20
Presenting: Zack Berke.
Gene chips, Regulatory networks, and sequencing by hybridization
[slides] [more slides] (Powerpoint)
Reading:
- Identifying Gene Regulatory Networks from Experimental Data, T. Chen, V. Filkov, S. S. Skiena (RECOMB'99)
- On the Power of Universal Bases in Sequencing by Hybridization, F. P. Preparata, A. M. Frieze, E. Upfal (RECOMB'99)
April 25
Presenting: Michael Johnson.
Distance Geometry

Reading:
April 27
Presenting: David Wagner.
Distance Geometry (Continued)

Reading:
- B. Berger, J. Kleinberg, F.T. Leighton. Reconstructing a Three-Dimensional Model with Arbitrary Errors. Proc. 28th ACM Symposium on Theory of Computing, 1996. [Postscript].
May 2
Presenting: Chris Langmead.
Time-Frequency Analysis of Chemical Shift Dynamics in Protein NMR Data
- Reading: "Time-Frequency Analysis of Chemical Shift Dynamics in Protein NMR Data" by C. J. Langmead and B. R. Donald.
May 4
Presenting: Tony Yan.
Threading for NMR Structure Determination by Homology
Reading: Y. Xu, D. Xu, O. H. Crawford, J. R. Einstein, E. Serpersu : Protein Structure Determination using Protein Threading and Sparse NMR Data (RECOMB'2000).
May 9
A one-page written project proposal is due Today.
Presenting: Hany Farid.
Protein Design
Reading:
- Book chapter: Minimization or Maximization of functions. (from Gilbert Strang's Linear Algebra and it's Applications).
- Book chapter: Projections and least-squares approximations. (from Numerical Recipes in C.)
- A new approach to the design of uniquely folded thermally stable proteins, by X. Jiang, Hany Farid, E. Pistor, and Ramy Farid (Protein Science, 9:403-416, 2000). [PDF]
- Background reading:
  - Prediction and Evaluation of Side-chain Conformations for Protein Backbone Structures, P.S. Shenkin, H. Farid and J.S. Fetrow in Proteins: Structure, Function and Genetics, 26:323-352, 1996
May 11
Presenting: Jack Kelley.
Introduction to Experimental and Computational Issues in Mass Spectrometry for Structural and Molecular Biology
[Slides] (Powerpoint)
Reading:
- Siuzdak G. The emergence of mass spectrometry in biochemical research. Proc Natl Acad Sci U S A. 1994 Nov 22;91(24):11290-7. [PDF]
May 16
Presenting: Andrew Ko.
Mass Spec (continued).
Reading:
- Use of Mass Spectrometry fragmentation patterns of peptides to identify amino acid sequences in databases, J. Yates and J. Eng, US Patent No. 05538897.
- Direct analysis of protein complexes using mass spectrometry Link, et al. (Nature Biotechnology, Vol 17, 1999).
May 18
Presenting: David Wagner.
Mass Spec (continued)
Reading:
- P. Pevzner, V. Dancik, C. L. Tang: Mutation-Tolerant Protein Identification by Mass-Spectrometry (RECOMB'2000).
- "A Universal Algorithm for Fast and Automated Charge State Deconvolution of Electrospray Mass-to-Chage Ratio Specta", by Zhongqi Zhang and Alan C. Marshall (Am. Soc. for Mass Spec., Elsvier) 1997.
May 23
Presenting: Eunnok Sohn.
Algorithms for Mass Spec
Reading: Course notes on MS. (Gzipped PostScript). Don't forget to read the appendix!
- Based on: "Reducing Mass Degeneracy in SAR by MS (Structure-Activity Relation by Mass Spectrometry) by Stable Isotopic Labeling," (C. Bailey-Kellogg, J. Kelley, C. Stein, and B. R. Donald) The 8th International Conference on Intelligent Systems for Molecular Biology, (August 20-23, 2000) La Jolla, CA (Accepted; to appear).
May 25
Presenting: Tim Danford.
RNA Structure Prediction
- R. B. Lyngso, C. N. S. Pederson : Pseudonknots in RNA Secondary Structures (RECOMB'2000).
- E. Rivas and S. Eddy, "A dynamic programming algorithm for RNA structure prediction including pseudoknots," Journal of Molecular Biology, 285:2053-2068 (1999). [PDF]
- "Structure, Stability and Function of RNA Pseudoknots Involved in Stimulating Ribosomal Frameshifting," by David P. Giedroc*, Carla A. Theimer and Paul L. Nixon J. Mol. Bio. (2000) 298:167-185. [PDF]
Tuesday, May 30
Last day of class
Final Projects are due Today.
Presenting: Elisheva Werner-Reiss (elishev@cs.huji.ac.il).
Topic: Generalized Convolution for Biopolymers
Reading:
- Greg Chirikjian, "Conformational statistics of macromolecules using generalized convolution".
- Greg Chirikjian and Y. Wang, "Conformational statistics of stiff macromolecules as solutions to PDEs on the rotation and motion groups".

Some other papers we may read

Whitepaper on Advanced Computational Structural Genomics (read the long version, not the "lite" version).
Fast detection of common substructure in proteins, P. Chew, K. Kedem, J. Kleinberg, and D. Huttenlocher (RECOMB'99).
Rick Lathrop Lab
For Wolfson-Nussinov work on geometric hashing for protein complexes, take a look at
- A book chapter (general intro): http://www.math.tau.ac.il/~wolfson/papers/elsev-chap98.ps.gz and
- paper (html) "Examination of shape complementarity in docking of Unbound proteins" by Raquel Norel, Donald Petrey, Haim J. Wolfson, Ruth Nussinov in Proteins: Structure, Function, and Genetics Volume 36, Issue 3, 1999. Pages: 307-317: http://www3.interscience.wiley.com/cgi-bin/fulltext/66000929/FTSTART
- or PDF version: http://www3.interscience.wiley.com/cgi-bin/fulltext?ID=66000929&PLACEBO=IE.pdf

Some Relevant WWW Links

AMMP.

AMMP is a modern full-featured molecular mechanics, dynamics and modeling program. It can manipulate both small molecules and macromolecules including proteins, nucleic acids and other polymers. In addition to standard features, like numerically stable molecular dynamics, fast multipole method for including all atoms in the calculation of long range potentials and robust structural optimizers, it has a flexible choice of potentials and a simple yet powerful ability to manipulate molecules and analyze individual energy terms. One major advantage over many other programs is that it is easy to introduce non-standard polymer linkages, unusual ligands or non-standard residues. Adding missing hydrogen atoms and completing partial structures, which are difficult for many programs, are straightforward in AMMP.

Read the white paper on Advanced Computational Structural Genomics

Computational biology research at Dartmouth.

Check out Donald Lab Papers at

RECOMB'99

Intelligent Systems in Molecular Biology (ISMB) (all meetings).

Dartmouth M.D.-Ph.D. Program

Web sites of interest to structural biologists.

A large resource page on computational biology at George Mason University.

A large resource page on bioinformatics at the Institut Pasteur.

CARB Biocomputing Resources.

A list of protein folding groups on the web.

The WWW Virtual Library page on biomolecules.

Donald Lab.

The Journal of Computer-Aided Molecular Design

Some resources and descriptions of problems in Computational Biology.

Notes
Related Resources on the World Wide Web

General Notes

Muscle-Specific Regulation of Transcription: A Catalog of Regulatory Elements by Laura L. L-pez and James W. Fickett presents a summary of published information on muscle-specific transcriptional regulation.

Pedro's BioMolecular Research Tools is a collection of WWW links to information and services useful to molecular biologists. It provides links to molecular biology search and analysis tools; bibliographic, text, and Web search services; guides and tutorials; and biological and biochemical journals and newsletters.

The World Wide Web Virtual Library: Biosciences points to virtual library pages for Biomolecules, and Biochemistry and Molecular Biology. Each of these pages presents a long list of Web resources. The World Wide Web Virtual Library Biomolecules covers molecular sequence and structure databases, metabolic pathway databases, and other lists of Web resources. The World Wide Web Virtual Library: Biochemistry and Molecular Biology is a list of resources listed by provider.

Cell & Molecular Biology Online is a well-organized list of Web resources for cell and molecular biologists. For each resource, a brief description is provided.

CSUBIOWEB, the California State University Biological Sciences Web server, provides links to other Web sites on cell biology and molecular biology.

The Dictionary of Cell Biology (London: Academic Press, 1995) defines transcription, leucine zipper, and other terms used in this research commentary.

Biotech Life Science Dictionary is a free resource that defines terms in biochemistry, biotechnology, botany, cell biology, and genetics, including terms used in this research commentary.

Protein Synthesis is a tutorial on the processes involved in Protein Synthesis, starting from the genetic information in DNA, through transcription to produce messenger RNA, and translation of mRNA to a polypeptide. This tutorial is a section of Principles of Protein Structure Using the Internet, a Birkbeck College (University of London) accredited Advanced Certificate course.

Numbered Notes

Reading the Messages in Genes describes transcription and provides a diagram. This page is a unit of Access Excellence, a national educational program sponsored by Genentech that provides high school biology teachers access to their colleagues, scientists, and critical sources of new scientific information via the Web.
The MIT Biology Hypertextbook is a Web-based textbook developed for introductory biology courses at MIT. Central Dogma provides an illustrated description of the process of transcription.
DNA binding proteins, enhancers, and the control of gene expression describes transcription and transcription factors. This page was developed by Ronald R. D. Croy as a component of Course Notes for Molecular Genetics I Lectures.
Control of Gene Expression in Eukaryotes by Phillip McClean is a tutorial on gene regulation. The Transcription Complex provides a brief discussion of transcription factors.
The Mechanisms of Gene Regulation are outlined in Microbial Genetics Lecture Notes, developed by L. S. Pierson III and C. Kennedy for a class at the University of Arizona.
The Wolberger Lab lists publications of Cynthia Wolberger and her co-workers.
Introduction to the Metazoa describes the metazoan phyla. This introduction is a chapter of The Phylogeny of Life, an online exhibit developed by the University of California Museum of Paleontology.
Protein Zippers describes the leucine zipper and provides an illustration.
Barbara Graves' research is described and selected publications are listed on the Huntsman Cancer Institute Web page at the University of Utah.

Some Useful References for the Course

Protein Science

Introduction to Protein Structure, Branden, C. and Tooze, J. (1991) Garland Publishing, New York
Proteins, Creighton, T.E. (1993) 2nd edition, W.H. Freeman & Co., New York
Principles of Protein Structure, Schulz, G.E. and Schirmer, R.H. (1979) Springer-Verlag, New York
Protein Structure - New Approaches to Disease and Therapy, Perutz, M. (1992) W.H. Freeman & Co., New York
Enzyme Structure and Mechanism, Fersht, A.R. (1976) 2nd ed., pub. W.H.Freeman & Co., New York

Biochemistry

Biochemistry, Stryer, L., (1995) 4th edition, W.H. Freeman & Co., New York
Biochemistry, Voet, D. and Voet, J.G. (1995) 2nd edition, John Wiley & Sons, New York
Principles of Biochemistry, Zubay, G.L., Parson, W.W. and Vance, D.E. (1995) Wm. C. Brown, Dubuque, Iowa

Cell Biology

Molecular Cell Biology, Darnell, J., Lodish, H. and Baltimore, D. (1995) 3rd edition, W.H. Freeman & Co., New York
Molecular Biology of The Cell, Alberts, B., Bray, D., Lewis, J., Raff, M., Roberts, K. and Watson, J.D. (1994) 3rd edition, Garland Publishing, New York

Hypertextbooks

BioComputing, for the VSNS-Biocomputing Division Course

Biology, developed by Shane Crotty, MIT

Course/Tutorial on Cell Biology, Mark Dalton, Cray Research

UK Mirror at UMIST

Principles of Biochemistry, Horton, Moran, Ochs, Rawn, Scrimgeour

Help with PDF files

PDF Hints
Are you getting "There was a problem processing a page" or "This file contains information not understood by the viewer" or other errors that keep you from viewing a PDF file? You must upgrade to version 3 of the Adobe Acrobat Reader software. Version 2 is no longer compatible with the PDFs for this course.

Return to top of page