MB&B 452a / 752a2
Survey, "Demographics", Projects, Intro. lecture [html] [pdf], Sequences lectures [html] [pdf], Databases lectures [html] [pdf], Structures lectures [html] [pdf], Simulation lectures [html] [pdf], Fun Reading, Use of Overheads
Bioinformatics describes the computational analysis of gene sequences and protein structures on a large scale. Topics include sequence alignment, biological database design, geometric analysis of protein structure, and macromolecular simulation. [Blue Book Entry]
Meeting from 1:00-2:15 PM on Mondays and Wednesday, in Bass 305.
MB&B Department, Bass building, Yale University, New Haven, CT 06520
Bass 432A, Phone 203 432-6105, e-mail Mark.Gerstein@yale.edu
Office hours right after class
Handouts and readings with Joann Delvecchio <firstname.lastname@example.org>
J W Gibbs 309C, 203 432-5566.
Course e-mail list at email@example.com with Hypertext archive of course messages.
The bioinformatics module will follow a very similar progression to the course offered last spring.
(See, in particular, http://bioinfo.mbb.yale.edu/course/classes.)
Also, see other related on-line lectures.
If you're really motivated, take a look at http://bioinfo.mbb.yale.edu/jobs.
If you want to use the overheads in your own course, feel free, as long
as you give proper attribution.
(A number of the overheads were derived from related courses at Stanford and are so acknowledged.)
Most of the reading material is copyright and can NOT be freely distributed. It should not be accessible outside of Yale.
Please e-mail back to Mark.Gerstein@yale.edu
See overall "course demographics" based on survey plus first quiz.
2 short ones in class, probably for a third of the class. SIMPLE multiple choice questions that you should be able to answer from the lectures plus the main readings.
First quiz on Monday 8 November will cover Introduction and Sequences material.
Provisionally, second quiz on 1 December.
Basic Alignment via Dynamic Programming
Similarity (PAM) Matrices
Profiles, Motifs, HMMs
Probabilistic Scoring Schemes
Rapid Similarity Search: Fasta
Rapid Similarity Search: Blast
Practical Suggestions on Sequence Searching
Transmembrane helix predictions
Secondary Structure Prediction: Basic GOR
Secondary Structure Prediction: Other Methods
Assessing Secondary Structure Prediction
Features of Genomic DNA Sequence
 Chapter 3 from Gribskov, M. and Devereux, J. (1992). Sequence Analysis Primer. New York, Oxford University Press.
(Focus on dynamic programming section of this chapter.)
 Needleman, S. B. and Wunsch, C. D. (1971). "A general method applicable to the search for similarities in the amino acid sequence of two proteins." J. Mol. Biol. 48: 443-453.
(The original paper. Still pretty easy to read. Will be used in class.)
 Smith, T. F. and Waterman, M. S. (1981). "Identification of common molecular subsequences." J. Mol. Biol. 147: 195-197
(The original paper on local alignment. Not quite as easy to read, but introduces this important concept.)
 Alschul et al. (1998). "Gapped BLAST and PSI-BLAST: a new generation of protein database search programs," Nucleic Acids Res 1997 Sep 1;25(17):3389-402
 Altschul, S. F., Boguski,
M. S., Gish, W. and Wootton, J. C. (1994). Issues in searching molecular sequence
databases. Nature Genetics. 6(2): 119-29.
(Most important. A short overall review.)
 M Levitt & M Gerstein
(1998). A Unified Statistical Framework for Sequence Comparison and Structure
Comparison. Proceedings of the National Academy of Sciences USA 95:
(Understand the concept of P-value and the framework for deriving scoring statistics.)
 Pearson, W. R. (1996). Effective
Protein Sequence Comparison. Meth. Enz. 266: 227-259.
(Understand how the FASTA e-value is derived.)
 Eddy, S. R. (1996). "Hidden Markov models," Curr. Opin. Struc. Biol. 6, 361-365.
 Higgins, D. G., Thompson, J. D. & Gibson, T. J. (1996). "Using CLUSTAL for multiple sequence alignments," Methods Enzymol 266, 383-402.
Garnier, J., Gibrat, J. F. & Robson, B. (1996b). "GOR method for predicting protein secondary structure from amino acid sequence," Methods Enzymol 266, 540-53.
 King, R. D. & Sternberg, M. J. E. (1996). "Identification and application of the concepts important for accurate and reliable protein secondary structure prediction," Prot. Sci. 5, 2298-2310.
Frishman D, and Argos P. (1997) "The Future of Protein Secondary Structure Prediction Accuracy," Folding & Design 2:159-62.
(Controversial idea: secondary structure prediction to 80%?)
M Gerstein (1998). "Measurement of the Effectiveness of Transitive Sequence Comparison, through a Third ‘Intermediate’ Sequence," Bioinformatics 14: 707-14.
Structuring Information in Tables
Keys and Joins
Complex RDB encoding
Indexes and Optimization
Forms and Reports
Clustering & Trees
Function Classification and Orthologs
The Genomic vs. Single-molecule Perspective
Folds in Genomes, shared & common folds
Bulk Structure Prediction
Extent of Fold Assignment: the Bias Problem
Correcting for Biases with Sampling
Cross-tabulation, folds and functions
Analysis of Expression Data
Analysis of Other Whole Genome Datasets
 M Gerstein & W Krebs (1998). "A Database of Macromolecular Movements," Nuc. Acid. Res. 26:4280-4290.
 Korth & Silberschatz, Database System Concepts
(CS book on databases; Read pages 1 to 65 [sections 1.0 to mid-3.2] and pages 97 to 108 [part of section 4.1]. Some of the information on SQL is available from the on-line link below.)
Fred Tekaia, Antonio Lazcano & Bernard Dujon (1999). "The Genomic Tree as Revealed from Whole Proteome Comparisons," Genome Res. 9:550-557
 H Hegyi & M Gerstein (1999). "The Relationship between Protein Structure and Function: a Comprehensive Survey with Application to the Yeast Genome," J Mol. Biol. 228: 147-164.
 M Gerstein & H Hegyi (1998). "Comparing Microbial Genomes in terms of Protein Structure: Surveys of a Finite Parts List," FEMS Microbiology Reviews 22: 277-304.
M Gerstein (1998). "Patterns of Protein-Fold Usage in Eight Microbial Genomes: A Comprehensive Structural Census," Proteins 33: 518-534.
** http:// bioinfo.mbb.yale.edu/course/private-xxxx/proteins_33_518.pdf
(This is an example of the application of large-scale, database-style calculations.)
Tomb, J.-F., White, O., Kerlavage, A. R., Clayton, R. A., Sutton, G. G., Fleischmann, R. D., Ketchum, K. A., Klenk, H. P., Gill, S., Dougherty, B. A., Nelson, K., Quackenbush, J., Zhou, L., Kirkness, E. F., Peterson, S., Loftus, B., Richardson, D., Dodson, R., Khalak, H. G., Glodek, A., McKenney, K., Fitzegerald, L. M., Lee, N., Adams, M. D., Hickey, E. K., Berg, D. E., Gocayne, J. D., Utterback, T. R., Peterson, J. D., Kelley, J. M., Cotton, M. D., Weidman, J. M., Fujii, C., Bowman, C., Watthey, L., Wallin, E., Hayes, W. S., Borodovsky, M., Karp, P. D., Smith, H. O., Fraser, C. M. & Venter, J. C. (1997). "The complete genome sequence of the gastric pathogen Helicobacter pylori," Nature 388, 539-547.
(This research article describes one of the recent genome sequences.)
Cavalli-Sforza, L. & Edwards, S. (1967). "Phylogenetic analysis: models and estimation procedures," Evolution 21, 550-570.
M Gerstein (1998). "How Representative are the Known Structures of the Proteins in a Complete Genome? A Comprehensive Structural Census," Folding & Design 3: 497-512.
Fitch, W. M. (1971). "Toward defining the course of evolution: minimum change for a specific topology," Syst. Zool. 20, 406-416.
Short review by R Young at MIT on Gene Chips, http://bioinfo.mbb.yale.edu/mbb452a/reading/young-tigs-chips.pdf
Swofford et al. (1994). "Phylogeny reconstruction," In Molecular Systematics (2nd ed.), Sinauer Press.
(This book chapter is a good reference thought not a neccessary reading.)
Overheads [html] [pdf 4.8Mb]
What Structures Look Like?
Structural Alignment by Iterated Dynamic Programming
Scoring Structural Similarity
Relation of Sequence Similarity to Structural and Functional Similarity
Calculation of Surface Area
Calculation of Volume
Standard Volumes and Radii
Structure Alignment Required Reading Holm, L. and Sander, C. (1993). Protein Structure Comparison by Alignment of Distance Matrices. J. Mol. Biol. 233: 123-128.
(A different method of structural alignment, which differs more from sequence alignment.)
 M Gerstein & M Levitt (1998). "Comprehensive Assessment of Automatic Structural Alignment against a Manual Standard, the Scop Classification of Proteins," Protein Science 7: 445-456.
(Understand the method, not results, in this paper OR in Gerstein & Levitt (1996), below)
Geometry Required Reading
 J Tsai, R Taylor, C Chothia & M Gerstein (1999). "The Packing Density in Proteins: Standard Radii and Volumes," J. Mol. Biol. 290: 253-266.
 M Gerstein & F M Richards, "Protein Geometry: Volumes, Areas, and Distances," (2000) chapter 22 of volume F of the International Tables for Crystallography ("Molecular Geometry and Features" in "Macromolecular Ccrystallography")
Extra Structures Reading
Taylor, W. R. & Orengo, C. A. (1989). Protein Structure Alignment. J. Mol. Biol. 208, 1-22.
Kuntz, I. D. (1992). Structure-Based Strategies for Drug Design and Discovery. Science 257, 1078-1082.
(Docking. See link below for more information.)
Richards, F. M. (1977). Areas, Volumes, Packing, and Protein Structure. Ann. Rev. Biophys. Bioeng. 6, 151-76.
Richards, F. M. (1974). The Interpretation of Protein Structures: Total Volume, Group Volume Distributions and Packing Density. J. Mol. Biol. 82, 1-14.
(Original Application of Voronoi Method to Proteins. See Int. Tabl. document above for more details on method.)
Pattabiraman, N., Ward, K.B. and Fleming, P.J. (1995) Occluded Molecular Surface: Analysis of Protein Packing, Journal of Molecular Recognition, 8:334-344
http://csbmet.csb.yale.edu/userguides/datamanip/os/os_descrip.html -- OS
Joan Pontius, Jean Richelle, Shoshana J. Wodak (1996). Deviations from Standard Atomic Volumes as a Quality Measure for Protein Crystal Structures. Journal of Molecular Biology 264: 121-136.
Barry Cipra (1998). “Packing Challenge Mastered At Last,” Science 281: 1267
Simon Singh (1998). “Mathematics ‘Proves’ What the Grocer Always Knew,” New York Times (August 25).
Basic Forces: Electrostatics
Bonds as Springs
Energy and Entropy
Lattice Models and Simplification
 M Gerstein & M Levitt (1998). "Simulating Water and the Molecules of Life," Scientific American 279: 100-105.
 McCammon, J. A. & Harvey, S. C. (1987). Dynamics of Proteins and Nucleic Acids. Cambridge UP.
 Honig, B. & Nicholls, A. (1995). Classical electrostatics in biology and chemistry. Science 268, 1144-9.
Information on Liquid Simulation Methods (excerpted from a thesis, 1992)
Levitt, M. (1983). Protein folding by restrained energy minimization and molecular dynamics. J Mol Biol 170, 723-64.
Allen, M. P. & Tildesley, D. J. (1987). Computer Simulation of Liquids. Claredon Press, Oxford. (A good reference.)
Karplus, M. & McCammon, J. A. (1986). The dynamics of proteins. Sci. Am. 254, 42-51. (A good reference.)
Duan, Y. & Kollman, P. A. (1998). Pathways to a protein folding intermediate observed in a 1-microsecond simulation in aqueous solution Science 282, 740-4.
Sharp, K. (1999). Electrostatic Interactions in Proteins. In International Tables for Crystallography, International Union of Crystallography, Chester, UK.
Dill, K. A., Bromberg, S., Yue, K., Fiebig, K. M., Yee, D. P., Thomas, P. D. & Chan, H. S. (1995). Principles of protein folding--a perspective from simple exact models. Protein Sci 4, 561-602.
Franks, F. (1983). Water. The Royal Society of Chemistry, London. Pages 35-56.
"Fathering life and other feats," Economist, 2 February 1999
(About synethetized M. genitalium)
"The Gutenberg Internet," Wall Street Jounal, June 11, 1999
"The hot new job in agriculture is bioinformatics," Work Week, Wall
Street Jounal, August 17, 1999, A1
Antonio Regalado (1999), "Mining the Genome," MIT TechReview, Sept/Oct. issue.
Charles C. Mann, "Biotech Goes Wild," TechReview, July/August
DAVID STIPP, "GENE CHIP BREAKTHROUGH, FORTUNE, 03/31/1997
Economist, 6/28/99, "Science & Technology: Drowning in data"
GEORGE JOHNSON, "Searching for the Essence of the World Wide Web,"
April 11, 1999
HENRY FOUNTAIN, "Hiding Secret Messages Within Human Code," New
York Times, June 22, 1999, F5
J L Weldon. "A Career in Data Modeling," Byte, June 1997
(Practical hands-on discussion of data modeling in commercial context, many of the same issues apply in bioinformatics.)
J L Weldon. "Data Warehouse Building Blocks," Byte, January 1997
J L Weldon. "Warehouse Cornerstones," Byte, January 1997
(Other, less relevant articles, on the some of the practical hardware issues in database design.)
J L Weldon. "RDBMSes Get a Make-Over," Byte, April 1997
(Practical discussion of what an object database is.)
Johnson, G. (1997). "Proteins Outthink Computers in Giving Shape to Life,"
New York Times. March 25, 1997, C1.
Johnson, G. (1997). "Proteins Outthink Computers in Giving Shape to Life,"
New York Times. March 25, 1997, C1.
L Hunter (ed), AI and Molecular Biology, AAAI Press (A new intro. text)
L. Fisher (1999). "Surfing the Human Genome; Data Bases of Genetic Code Are Moving to the Web," New York Times. 09/20/99, C1
Langreth, R. (1997). "Scientists Unlock Sequence Of Ulcer Bacterium's Genes,"
Wall Street Journal. 7 August.
Lisa Belkin, "Splice Einstein and Sammy Glick. Add a Little Magellan,"
New York Times Magazine, 08/23/98, Page 26 (Article on J C Venter)
M Gerstein (1999). "E-publishing on the Web: Promises, Pitfalls, and Payoffs
for Bioinformatics," Bioinformatics 15: 429-431.
MARLISE SIMONS, "Team of Scientists to Prepare a Rolodex of Life on Earth,"
New York Times, July 27, 1999, F2
N Wade, "Who'll Sequence Human Genome First? It's Up to Phred," New
York Times, March 23, 1999, F2
NICHOLAS WADE, "Cambridge Lab Keeps Britain Ahead in Genome Stakes,"
New York Times, October 6, 1998
NICHOLAS WADE, "Gains Are Reported in Decoding Genome," New York
Times, May 22, 1999, A4
PAMELA LICALZI O'CONNELL "Beyond Geography: Mapping Unknown of Cyberspace,"
New York Times, September 30, 1999
Pollack, A. (1998). Drug Testers Turn to'Virtual Patients' as Guinea Pigs.
New York Times, Nov. 10
Primer on Molecular Genetics from the DOE
ROBERT LANGRETH, "CuraGen's Finds 55,000 Variations Of Genes, Auguring
Tailored Drugs," Wall Street Jounal, August 16, 1999
Steven Vogel, "Academically Correct Biological Science", American Scientist,
Tanouye, E. & Langreth, R. (1998). "SmithKline-Glaxo Deal Driven By the
Hunt for Human Genes," Wall Street Journal. February 2.
Wade, N. (1997). "Now Playing at a Nearby Lab : 'Revenge of the Fly People,'"
New York Times. 05/20/97, C1.
Wade, N. (1997). "Scientists Map Ulcer Bacterium's Genetic Code," New York
Times. August 7.
Wade, N. (1997). "Thinking Small Paying Off Big In Gene Quest," New York
Times. 02/03/97, A1.
WILLIAM K. STEVENS, "Rearranging the Branches on a New Tree of Life,"
August 31, 1999, F1
The DNA-mouse image is adapted from the GCB-98 homepage. What's wrong with the adaptation?