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Social behavior of proteins?. Rui Alves. Organization of the talk. Social behavior of the protein?!?!?!? Using meta text analysis Using phylogenetic profiling Using pathway homology Using protein docking Using microarray data Using protein interaction data. Proteins do not work alone!. - PowerPoint PPT Presentation
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Social behavior of proteins?
Rui Alves
Organization of the talk
• Social behavior of the protein?!?!?!?
• Using meta text analysis
• Using phylogenetic profiling
• Using pathway homology
• Using protein docking
• Using microarray data
• Using protein interaction data
Proteins do not work alone!
Networks of “interactions” predict global function
• Having the network of proteins/genes in which your protein/gene is inserted provides predictive information:
– Which cellular pathways or processes is your protein/gene likely to be involved in
Organization of the talk
• Social behavior of the protein?!?!?!?
• Using meta text analysis
• Using phylogenetic profiling
• Using pathway homology
• Using protein docking
• Using microarray data
• Using protein interaction data
Publication databases are source of information
Meta text databases create social models from publication analysis
iHOP is a sofisticated context analysis motor
How does meta-text analysis create networks?
Literature database
Gene names
database
Language rules
database
scripts
Entry
Gene list Rule list
Server/
Program
Your genes
List of entries mentioning your gene
e.g Ste20e.g activate,
inhibit rescue
Organization of the talk
• Social behavior of the protein?!?!?!?• Meta text analysis• Evolutionary based protein interaction
prediction• Using pathway homology• Using protein docking• Using microarray data• Using protein interaction data
Proteins that have coevolved share a function
• If protein A has co-evolved with protein B, they are likely to be involved in the same process
• Looking for proteins that coevolved will help prediction social networks of proteins
• There are many methods to look for co-evolution of proteins– Phylogenetic profiling, gene neighbourhoods,
gene fusion events, phylogenetic trees…
Creating phylogenetic profiles
Database of proteins in fully sequenced genomes
Homology search against each genome
Sequence of each proteinDatabase of proteins in one genome
Target Genome
Homologue in Genome 1?
Homologue in Genome 2?
…
Protein A Y N …
… … … …
Database of profiles for each protein in each organism
Using phylogenetic profiles to predict protein interactions
Your Sequence (A) Server/
Program
Database of profiles for each protein in each organism
Database of proteins in fully sequenced genomes
Protein id A
Target Genome
Homologue in Genome 1?
Homologue in Genome 2?
…
A
B
C
…
Y
N
Y
…
N
Y
N
…
…
…
…
…
A B
00i/number of genomes<1C
1j/number of genomes
A 1
C 0.9
… …
B 0.11
… …
Proteins (A and C) that are present and absent in the same set of genomes are likely to be involved in the same process and therefore interact
Similarly, if protein A is absent in all genomes in which protein B is present there is a likelihood that they perform the same function! 2
Calculate coincidence index
How to do it?
• Download genomes
• Use blast for homology
• Use perl for homology processing and coincidence index calculations
Proteins A and B are in a conserved relative position in most genomes which is an
indication that they are likely to interact
Syntheny/Conservation of gene neighborhoods
Genome 1
Genome 2
Genome 3
Genome …
Protein A Protein B Protein C Protein D
Protein A Protein BProtein C Protein D
Protein AProtein B Protein CProtein D
…
Protein A Protein B Protein C Protein D
Which of these proteins “interact”?
How to do it?
• Download genomes
• Use perl for analysis
Gene fusion events
Genome 1
Genome 2
Genome 3
Genome …
Protein A Protein BProtein C Protein D
Protein A Protein B Protein C Protein D
Protein AProtein B Protein CProtein D
…
Protein A Protein B Protein C Protein D
Which of these proteins interact?Proteins A and B have suffered gene fusion
events in at least some genomes, which is an indication that they are likely to interact
How to do it?
• Download genomes
• Use perl for analysis
Building phylogenetic trees of proteins
Genome 1
Genome 2
Genome 3
Genome …
Protein A Protein B Protein C Protein D
Protein A Protein BProtein C Protein D
Protein AProtein B Protein CProtein D
…Get sequence of all homogues, align and
build a phylogenetic tree
Phylogenetic trees represent the evolutionary history of homologue
genes/proteins based on their sequence
Distance based phylogenetic trees
ACTDEEGGGGSRGHI…A-TEEDGGAASRGHI…ACFDDEGGGGSRGHL……
A1
A2
A3
…
A1
A2
A3
A1
5 substitutions 3 substitutionsA2
A3
8 substitutions
A2
A3
A1
3
5
Maximum likelihood phylogenetic trees
ACTDEEGGGGSRGHI…A-TEEDGGAASRGHI…ACFDDEGGGGSRGHL……
Alignment Probability of aa substitution
A - E D …
A 1 0.01 0.2 0.09 …
- 0.01 1 0.0001 0.0001 …
E 0.2 0.0001 1 0.5
D 0.09 0.0001 0.5 1
…
Maximum likelihood phylogenetic trees
ACTDEEGGGGSRGHI…A-TEEDGGAASRGHI…ACFDDEGGGGSRGHL……
AlignmentA1
A2
A3
A1
5 substitutions
3 substitutions
A2
A3
8 substitutions
p(1,2)
p(1,3)
p(2,3)
p(2,3)<p(1,2)<p(1,3)
A1
A3
A2
A2
A3
A1
Similarity of phylogenetic trees indicates “interaction” between proteins
A1
B2
C1 D1
A2
A3
… …
…
B1
B3
C2
C3
…
D3
D2Proteins A and B have similar evolutionary trees and thus are likely to “interact”
How to do it?
• Download genomes
• Use blast,… for analysis
• Use Clustal, Phylip, PAUP, … for tree building
Organization of the talk
• Social behavior of the protein?!?!?!?
• Using meta text analysis
• Using phylogenetic profiling
• Using pathway homology
• Using protein docking
• Using microarray data
• Using protein interaction data
Pathway homology
Database of protein
sequences in
genomes
Database of
pathways in
genomes
Database of
interactions in
genomes
Server/
Program
Your Sequence
Homologue(s)
Output
Pathway homology complements protein homology
Organization of the talk
• Social behavior of the protein?!?!?!?
• Using meta text analysis
• Using phylogenetic profiling
• Using pathway homology
• Using protein docking
• Using microarray data
• Using protein interaction data
What is protein docking?
Protein
AProtein B
Protein
AProtein BProtein
A
Pro
tein B
Protein
A
Protein B
Same area of interaction
Protein
AProtein B
Protein
A
Protein BPositive Negative
Negative
Best Docking
Caveats of using protein docking to predict interaction
Protein
AProtein B
Protein
C
Glycolisys DNA synthesis
• Proteins may not come into contact in the cell although if they did they could interact
• Very heavy computationaly
When shoudl we use protein docking to predict network structure?
• When we have a group of proteins that are known to be involved in the same function and we want to predict how the different proteins interact with each other
How to do it?
• Download structures or create structure predictions
• Use GRAMM, HEX, …
Organization of the talk
• Social behavior of the protein?!?!?!?
• Using meta text analysis
• Using phylogenetic profiling
• Using pathway homology
• Using protein docking
• Using microarray data
• Using protein interaction data
Predicting protein interactions using micro array data
cells
cells
Stimulum
Purify cDNA
Purify cDNA Compare cDNA levels of
corresponding genes in the different
populations
Genes overexpressed
as a result of stimulus
Genes underexpressed
as a result of stimulus
Genes with expression
independent of stimulus
Group of proteins involved in response
to the stimulus
Organization of the talk
• Social behavior of the protein?!?!?!?
• Using meta text analysis
• Using phylogenetic profiling
• Using pathway homology
• Using protein docking
• Using microarray data
• Using protein interaction data
Predicting protein networks using protein interaction data
Database of protein
interactions
Server/
Program
Your Sequence (A)
A
BC
D E
FContinue until you are satisfied
or completed the network
Summary
• Social behavior of the protein?!?!?!?
• Using meta text analysis
• Using phylogenetic profiling
• Using pathway homology
• Using protein docking
• Using microarray data
• Using protein interaction data