Download 2 - CABM Structural Bioinformatics Laboratory

Mark Gerstein, Yale University
bioinfo.mbb.yale.edu/mbb452a
1 (c) Mark Gerstein, 1999, Yale, bioinfo.mbb.yale.edu
BIOINFORMATICS
Introduction
Biological
Data
+
Computer
Calculations
2 (c) Mark Gerstein, 1999, Yale, bioinfo.mbb.yale.edu
Bioinformatics
• (Molecular) Bio - informatics
Bioinformatics is conceptualizing biology in terms of
molecules (in the sense of physical-chemistry) and
then applying “informatics” techniques (derived
from disciplines such as applied math, CS, and
statistics) to understand and organize the
information associated with these molecules, on a
large-scale.
• Bioinformatics is a practical discipline with many
applications.
3 (c) Mark Gerstein, 1999, Yale, bioinfo.mbb.yale.edu
What is Bioinformatics?
What is the Information?
Molecular Biology as an Information Science
DNA
-> RNA
-> Protein
-> Phenotype
-> DNA
• Molecules

Sequence, Structure, Function
• Processes

Mechanism, Specificity, Regulation
• Central Paradigm
for Bioinformatics
Genomic Sequence Information
-> mRNA (level)
-> Protein Sequence
-> Protein Structure
-> Protein Function
-> Phenotype
• Large Amounts of Information


Standardized
Statistical
•Most cellular functions are performed or
facilitated by proteins.
•Primary biocatalyst
•Cofactor transport/storage
•Mechanical motion/support
•Genetic material
•Information transfer (mRNA)
•Protein synthesis (tRNA/mRNA)
•Some catalytic activity
•Immune protection
•Control of growth/differentiation
(idea from D Brutlag, Stanford, graphics from S Strobel)
4 (c) Mark Gerstein, 1999, Yale, bioinfo.mbb.yale.edu
• Central Dogma
of Molecular Biology
Molecular Biology Information - DNA
 Coding or Not?
 Parse into genes?
 4 bases: AGCT
 ~1 K in a gene,
~2 M in genome
atggcaattaaaattggtatcaatggttttggtcgtatcggccgtatcgtattccgtgca
gcacaacaccgtgatgacattgaagttgtaggtattaacgacttaatcgacgttgaatac
atggcttatatgttgaaatatgattcaactcacggtcgtttcgacggcactgttgaagtg
aaagatggtaacttagtggttaatggtaaaactatccgtgtaactgcagaacgtgatcca
gcaaacttaaactggggtgcaatcggtgttgatatcgctgttgaagcgactggtttattc
ttaactgatgaaactgctcgtaaacatatcactgcaggcgcaaaaaaagttgtattaact
ggcccatctaaagatgcaacccctatgttcgttcgtggtgtaaacttcaacgcatacgca
ggtcaagatatcgtttctaacgcatcttgtacaacaaactgtttagctcctttagcacgt
gttgttcatgaaactttcggtatcaaagatggtttaatgaccactgttcacgcaacgact
gcaactcaaaaaactgtggatggtccatcagctaaagactggcgcggcggccgcggtgca
tcacaaaacatcattccatcttcaacaggtgcagcgaaagcagtaggtaaagtattacct
gcattaaacggtaaattaactggtatggctttccgtgttccaacgccaaacgtatctgtt
gttgatttaacagttaatcttgaaaaaccagcttcttatgatgcaatcaaacaagcaatc
aaagatgcagcggaaggtaaaacgttcaatggcgaattaaaaggcgtattaggttacact
gaagatgctgttgtttctactgacttcaacggttgtgctttaacttctgtatttgatgca
gacgctggtatcgcattaactgattctttcgttaaattggtatc . . .
. . .
caaaaatagggttaatatgaatctcgatctccattttgttcatcgtattcaa
caacaagccaaaactcgtacaaatatgaccgcacttcgctataaagaacacggcttgtgg
cgagatatctcttggaaaaactttcaagagcaactcaatcaactttctcgagcattgctt
gctcacaatattgacgtacaagataaaatcgccatttttgcccataatatggaacgttgg
gttgttcatgaaactttcggtatcaaagatggtttaatgaccactgttcacgcaacgact
acaatcgttgacattgcgaccttacaaattcgagcaatcacagtgcctatttacgcaacc
aatacagcccagcaagcagaatttatcctaaatcacgccgatgtaaaaattctcttcgtc
ggcgatcaagagcaatacgatcaaacattggaaattgctcatcattgtccaaaattacaa
aaaattgtagcaatgaaatccaccattcaattacaacaagatcctctttcttgcacttgg
5 (c) Mark Gerstein, 1999, Yale, bioinfo.mbb.yale.edu
• Raw DNA Sequence
Molecular Biology Information:
Protein Sequence
 ACDEFGHIKLMNPQRSTVWY
but not BJOUX
Z
• Strings of ~300 aa in an average protein (in bacteria),
~200 aa in a domain
• ~200 K known protein sequences
d1dhfa_
d8dfr__
d4dfra_
d3dfr__
LNCIVAVSQNMGIGKNGDLPWPPLRNEFRYFQRMTTTSSVEGKQ-NLVIMGKKTWFSI
LNSIVAVCQNMGIGKDGNLPWPPLRNEYKYFQRMTSTSHVEGKQ-NAVIMGKKTWFSI
ISLIAALAVDRVIGMENAMPWN-LPADLAWFKRNTL--------NKPVIMGRHTWESI
TAFLWAQDRDGLIGKDGHLPWH-LPDDLHYFRAQTV--------GKIMVVGRRTYESF
d1dhfa_
d8dfr__
d4dfra_
d3dfr__
LNCIVAVSQNMGIGKNGDLPWPPLRNEFRYFQRMTTTSSVEGKQ-NLVIMGKKTWFSI
LNSIVAVCQNMGIGKDGNLPWPPLRNEYKYFQRMTSTSHVEGKQ-NAVIMGKKTWFSI
ISLIAALAVDRVIGMENAMPW-NLPADLAWFKRNTLD--------KPVIMGRHTWESI
TAFLWAQDRNGLIGKDGHLPW-HLPDDLHYFRAQTVG--------KIMVVGRRTYESF
d1dhfa_
d8dfr__
d4dfra_
d3dfr__
VPEKNRPLKGRINLVLSRELKEPPQGAHFLSRSLDDALKLTEQPELANKVDMVWIVGGSSVYKEAMNHP
VPEKNRPLKDRINIVLSRELKEAPKGAHYLSKSLDDALALLDSPELKSKVDMVWIVGGTAVYKAAMEKP
---G-RPLPGRKNIILS-SQPGTDDRV-TWVKSVDEAIAACGDVP------EIMVIGGGRVYEQFLPKA
---PKRPLPERTNVVLTHQEDYQAQGA-VVVHDVAAVFAYAKQHLDQ----ELVIAGGAQIFTAFKDDV
d1dhfa_
d8dfr__
d4dfra_
d3dfr__
-PEKNRPLKGRINLVLSRELKEPPQGAHFLSRSLDDALKLTEQPELANKVDMVWIVGGSSVYKEAMNHP
-PEKNRPLKDRINIVLSRELKEAPKGAHYLSKSLDDALALLDSPELKSKVDMVWIVGGTAVYKAAMEKP
-G---RPLPGRKNIILSSSQPGTDDRV-TWVKSVDEAIAACGDVPE-----.IMVIGGGRVYEQFLPKA
-P--KRPLPERTNVVLTHQEDYQAQGA-VVVHDVAAVFAYAKQHLD----QELVIAGGAQIFTAFKDDV
6 (c) Mark Gerstein, 1999, Yale, bioinfo.mbb.yale.edu
• 20 letter alphabet
Molecular Biology Information:
Macromolecular Structure
 Almost all protein
(RNA Adapted From D Soll Web Page,
Right Hand Top Protein from M Levitt web page)
7 (c) Mark Gerstein, 1999, Yale, bioinfo.mbb.yale.edu
• DNA/RNA/Protein
Molecular Biology
Information:
Whole Genomes
Fleischmann, R. D., Adams, M. D., White, O., Clayton, R. A., Kirkness, E. F.,
Kerlavage, A. R., Bult, C. J., Tomb, J. F., Dougherty, B. A., Merrick, J. M., McKenney, K.,
Sutton, G., Fitzhugh, W., Fields, C., Gocayne, J. D., Scott, J., Shirley, R., Liu, L. I., Glodek, A.,
Kelley, J. M., Weidman, J. F., Phillips, C. A., Spriggs, T., Hedblom, E., Cotton, M. D.,
Utterback, T. R., Hanna, M. C., Nguyen, D. T., Saudek, D. M., Brandon, R. C., Fine, L. D.,
Fritchman, J. L., Fuhrmann, J. L., Geoghagen, N. S. M., Gnehm, C. L., McDonald, L. A.,
Venter, J. C. (1995). "Wholegenome random sequencing and assembly of Haemophilus influenzae rd."
Genome sequence now
Science 269: 496-512.
accumulate so quickly that,
(Picture adapted from TIGR website,
in less than a week, a single
http://www.tigr.org)
laboratory can produce
• Integrative Data
more bits of data than
1995, HI (bacteria): 1.6 Mb & 1600 genes done Shakespeare managed in a
1997, yeast: 13 Mb & ~6000 genes for yeast
lifetime, although the latter
1998, worm: ~100Mb with 19 K genes
make better reading.
Small, K. V., Fraser, C. M., Smith, H. O. &
1999: >30 completed genomes!
2003, human: 3 Gb & 100 K genes...
-- G A Pekso, Nature 401: 115-116 (1999)
8 (c) Mark Gerstein, 1999, Yale, bioinfo.mbb.yale.edu
• The Revolution Driving Everything
Young/Lander, Chips,
Abs. Exp.
Brown,
Botstein
marray,
Rel. Exp. over
Timecourse
Also: SAGE;
Samson and
Church, Chips;
Aebersold,
Protein
Expression
Snyder,
Transposons,
Protein Exp.
9 (c) Mark Gerstein, 1999, Yale, bioinfo.mbb.yale.edu
Gene Expression
Datasets: the
Transcriptome
Yeast Expression Data in
Academia:
levels for all 6000 genes!
Can only sequence genome
once but can do an infinite
variety of these array
experiments
at 10 time points,
6000 x 10 = 60K floats
telling signal from
background
(courtesy of J Hager)
10 (c) Mark Gerstein, 1999, Yale, bioinfo.mbb.yale.edu
Array Data
• Affymetrix
• Oligos
• Glass slides
 Pat brown
11 (c) Mark Gerstein, 1999, Yale, bioinfo.mbb.yale.edu
microarrays
Systematic Knockouts
Winzeler, E. A., Shoemaker, D. D.,
Astromoff, A., Liang, H., Anderson, K.,
Andre, B., Bangham, R., Benito, R.,
Boeke, J. D., Bussey, H., Chu, A. M.,
Connelly, C., Davis, K., Dietrich, F., Dow,
S. W., El Bakkoury, M., Foury, F., Friend,
S. H., Gentalen, E., Giaever, G.,
Hegemann, J. H., Jones, T., Laub, M.,
Liao, H., Davis, R. W. & et al. (1999).
Functional characterization of the S.
cerevisiae genome by gene deletion and
parallel analysis. Science 285, 901-6
2 hybrids, linkage maps
Hua, S. B., Luo, Y., Qiu, M., Chan, E., Zhou, H. &
Zhu, L. (1998). Construction of a modular yeast twohybrid cDNA library from human EST clones for the
human genome protein linkage map. Gene 215,
143-52
For yeast:
6000 x 6000 / 2
~ 18M interactions
12 (c) Mark Gerstein, 1999, Yale, bioinfo.mbb.yale.edu
Other WholeGenome
Experiments
• Information to
understand genomes
 Metabolic Pathways
(glycolysis), traditional
biochemistry
 Regulatory Networks
 Whole Organisms
Phylogeny, traditional
zoology
 Environments, Habitats,
ecology
 The Literature
(MEDLINE)
• The Future....
(Pathway drawing from P Karp’s EcoCyc, Phylogeny
from S J Gould, Dinosaur in a Haystack)
13 (c) Mark Gerstein, 1999, Yale, bioinfo.mbb.yale.edu
Molecular Biology Information:
Other Integrative Data
GenBank
Growth
Year
1982
1983
1984
1985
1986
1987
1988
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
GenBank Data
Base Pairs
Sequences
680338
606
2274029
2427
3368765
4175
5204420
5700
9615371
9978
15514776
14584
23800000
20579
34762585
28791
49179285
39533
71947426
55627
101008486
78608
157152442
143492
217102462
215273
384939485
555694
651972984
1021211
1160300687
1765847
2008761784
2837897
3841163011
4864570
8604221980
7077491
14 (c) Mark Gerstein, 1999, Yale, bioinfo.mbb.yale.edu
Large-scale
Information:
Internet
Hosts
 As important as the
increase in computer
speed has been, the
ability to store large
amounts of
information on
computers is even
more crucial
(Internet picture adapted
from D Brutlag, Stanford)
Num.
Protein
Domain
Structures
Structures in PDB
• Driving Force in
Bioinformatics
1979
1981
1983
1985
1987
1989
1991
4500
4000
3500
3000
2500
2000
1500
1000
500
0
1980
1993
1995
140
120
100
80
60
40
20
0
1985
1990
1995
CPU Instruction
Time (ns)
• CPU vs Disk & Net
15 (c) Mark Gerstein, 1999, Yale, bioinfo.mbb.yale.edu
Large-scale Information:
Exponential Growth of Data Matched by
Development of Computer Technology
The Next Step
after the sequence:
Proteomics
Expression
Analysis
Structural
Genomics,
Protein
Interactions
Step 1: The
genome
sequence and
genes
Pseudogenes, Regulatory
Regions, Repeats
Evolutionary Implications of Intergenic
Regions as Gene Graveyard
16 (c) Mark Gerstein, 1999, Yale, bioinfo.mbb.yale.edu
Comprehensive
Understanding of
Gene Function on
a Genomic Scale
17 (c) Mark Gerstein, 1999, Yale, bioinfo.mbb.yale.edu
The
next
step:
• Different Sequences Have the
Same Structure
• Organism has many similar genes
• Single Gene May Have Multiple
Functions
• Genes are grouped into Pathways
• Genomic Sequence Redundancy
due to the Genetic Code
• How do we find the
similarities?.....
Integrative Genomics genes  structures 
functions  pathways 
expression levels 
regulatory systems  ….
18 (c) Mark Gerstein, 1999, Yale, bioinfo.mbb.yale.edu
Organizing
Molecular Biology
Information:
Redundancy and
Multiplicity
“Prediction”
Bioinformatics
(focused on
individual genes
and structures)
19 (c) Mark Gerstein, 1999, Yale, bioinfo.mbb.yale.edu
Integrative Genomic
Surveys of Many Proteins vs
from Many Perspectives
• Understanding How Structures Bind Other Molecules (Function)
• Designing Inhibitors
• Docking, Structure Modeling
(From left to right, figures adapted from Olsen Group Docking Page at Scripps, Dyson NMR Group Web page at Scripps, and from Computational
Chemistry Page at Cornell Theory Center).
20 (c) Mark Gerstein, 1999, Yale, bioinfo.mbb.yale.edu
Major Application I:
Designing Drugs
Fold
Recognition
Docking &
Drug Design
Protein
Geometry
Protein
Flexibility
Secondary
Structure
Prediction
Homology
Modeling
Function E-literature
ClassSequence
ification Expression
Alignment
Clustering
Database
Design
Gene
Large-Scale
Prediction
Structure
Classification
Genome
Annotation
Genomic
Surveys
21 (c) Mark Gerstein, 1999, Yale, bioinfo.mbb.yale.edu
Bioinformatics
Subtopics
• (Molecular) Bio - informatics
Bioinformatics is conceptualizing biology in terms of
molecules (in the sense of physical-chemistry) and
then applying “informatics” techniques (derived
from disciplines such as applied math, CS, and
statistics) to understand and organize the
information associated with these molecules, on a
large-scale.
• Bioinformatics is a practical discipline with many
applications.
22 (c) Mark Gerstein, 1999, Yale, bioinfo.mbb.yale.edu
What is Bioinformatics?