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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 Server/ scripts Your genes Program Entry List of entries mentioning your gene Gene e.g Ste20 names database e.g activate, Language inhibit rules rescue database Gene list Rule list 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 Database of proteins in one genome Sequence of each protein Homology search against each 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) A 1 C 0.9 Server/ … … Program B Database of proteins in fully sequenced genomes 0.11 Target Homologue in Homologue in … … Genome … 2? Genome Genome 1? (A and absent of A ProteinsCalculate Y and C) that are present N …in the same setProtein are likely to be involved in the same…process and therefore id A B genomes N Y interact coincidence index C Y N … … … … … A if protein B CA is absent in all genomes in which protein Similarly, B isof Database i/number ofisgenomes<1 present there a likelihood that they perform the same profiles function!for 0j/number 1 of genomes 2 each protein in each organism How to do it? • Download genomes • Use blast for homology • Use perl for homology processing and coincidence index calculations Syntheny/Conservation of gene neighborhoods Genome 1 Protein A Genome 2 Protein C Protein A Protein B Protein C Protein D Protein A Protein B Protein D Protein B Protein C Protein D Proteins A and B are in a conserved relative Genome 3 Protein B Protein A Protein C Protein D position most genomes is an Whichinof these proteinswhich “interact”? indication that they are likely to interact Genome … … How to do it? • Download genomes • Use perl for analysis Gene fusion events Genome 1 Genome 2 Protein A Protein B Protein C Protein D Protein A Protein B Protein C Protein D Protein C Protein A Protein B Protein D Which of these proteins interact? Proteins A and B have suffered gene fusion Genome 3 in atProtein Protein B Protein A Protein C D events least some genomes, which is an indication that they are likely to interact Genome … … How to do it? • Download genomes • Use perl for analysis Building phylogenetic trees of proteins Genome 1 Protein A Protein B Protein C Protein D Phylogenetic trees represent the Genome evolutionary 2 homologue Protein D Protein C history Protein A of Protein B genes/proteins based on their sequence Genome 3 Protein B Protein A Protein C Protein D Genome … … Get sequence of all homogues, align and build a phylogenetic tree Distance based phylogenetic trees A1 A2 A3 … A2 A1 5 substitutions ACTDEEGGGGSRGHI… A-TEEDGGAASRGHI… ACFDDEGGGGSRGHL… … A1 A3 A3 3 substitutions A2 8 substitutions 5 A1 A3 3 A2 Maximum likelihood phylogenetic trees Alignment Probability of aa substitution A - E D … ACTDEEGGGGSRGHI… 0.01 0.2 0.09 … A-TEEDGGAASRGHI… A 1 ACFDDEGGGGSRGHL… - 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 A2 Alignment p(1,2) ACTDEEGGGGSRGHI… A-TEEDGGAASRGHI… ACFDDEGGGGSRGHL… … p(1,3) A1 5 substitutions A1 A3 3 substitutions p(2,3)<p(1,2)<p(1,3) A3 A2 A1 p(2,3) A3 A3 A1 A2 A2 8 substitutions Similarity of phylogenetic trees indicates “interaction” between proteins B1 A1 B2 A2 B3 A3 … … C3 D2 … Proteins A and B have similar evolutionary trees and thus are likely to “interact” … C2 C1 D1 D3 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 Your Sequence Server/ Program 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 A Protein B Protein B Protein B Best Docking Protein B Positive Protein A Protein A Protein B Protein A Protein A Negative Protein A Same area of interaction Protein B Negative Caveats of using protein docking to predict interaction Protein B Glycolisys Protein A Protein C 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 Group of proteins involved in response Purify cDNA Compare cDNA to the stimuluslevels of corresponding genes Purify cDNA in the different populations Stimulum Genes overexpressed as a result of stimulus Genes underexpressed as a result of stimulus cells Genes with expression independent of 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 Server/ Program Database of protein interactions A C D Your Sequence (A) E Continue until you are satisfied B or completed F 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