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