1. Sequence-Structure-Function Sequence Structure Function Threading Ab initio BLAST Folding: impossible but for the smallest structures Function prediction from structure – very difficult

2. Experimental Structural genomics Functional genomics Protein-protein interaction Metabolic pathways Expression data

5. Protein function groups Catalysis (enzymes) Binding – transport (active/passive) –Protein-DNA/RNA binding (e.g. histones, transcription factors) –Protein-protein interactions (e.g. antibody-lysozyme) –Protein-fatty acid binding (e.g. apolipoproteins) –Protein – small molecules (drug interaction, structure decoding) Structural component (e.g.  -crystallin) Regulation Signalling Transcription regulation Immune system Motor proteins (actin/myosin)

6. Energy difference upon binding Examples of protein interactions (and functional importance) include: Protein – protein (pathway analysis); Protein – small molecules (drug interaction, structure decoding); Protein – peptides, DNA/RNA (function analysis) The change in Gibb’s Free Energy of the protein-ligand binding interaction can be monitored and expressed by the following;  G =  H - T x  S (H=Enthalpy, S=Entropy and T=Temperature)

7. Protein function Many proteins combine functions Some immunoglobulin structures are thought to have more than 100 different functions (and active/binding sites) Alternative splicing can generate (partially) alternative structures

8. Protein function Active site / binding cleft Protein-protein interaction Shape complementarity

9. Protein function evolution Chymotrypsin

10. How to infer function Experiment Deduction from sequence –Multiple sequence alignment – conservation patterns –Homology searching Deduction from structure –Threading –Structure-structure comparison –Homology modelling

11. Mevalonate plays a role in epithelial cancers: it can inhibit EGFR

24. Metabolic networks Glycolysis and Gluconeogenesis Kegg database (Japan)

25. Gene Ontology (GO) Not a genome sequence database Developing three structured, controlled vocabularies (ontologies) to describe gene products in terms of: –biological process –cellular component –molecular function in a species-independent manner

26. The GO ontology

27. Gene Ontology Members FlyBase - database for the fruitfly Drosophila melanogaster Berkeley Drosophila Genome Project (BDGP) - Drosophila informatics; GO database & software, Sequence Ontology development Saccharomyces Genome Database (SGD) - database for the budding yeast Saccharomyces cerevisiae Mouse Genome Database (MGD) & Gene Expression Database (GXD) - databases for the mouse Mus musculus The Arabidopsis Information Resource (TAIR) - database for the brassica family plant Arabidopsis thaliana WormBase - database for the nematode Caenorhabditis elegans EBI GOA project : annotation of UniProt (Swiss-Prot/TrEMBL/PIR) and InterPro databases Rat Genome Database (RGD) - database for the rat Rattus norvegicus DictyBase - informatics resource for the slime mold Dictyostelium discoideum GeneDB S. pombe - database for the fission yeast Schizosaccharomyces pombe (part of the Pathogen Sequencing Unit at the Wellcome Trust Sanger Institute) GeneDB for protozoa - databases for Plasmodium falciparum, Leishmania major, Trypanosoma brucei, and several other protozoan parasites (part of the Pathogen Sequencing Unit at the Wellcome Trust Sanger Institute) Genome Knowledge Base (GK) - a collaboration between Cold Spring Harbor Laboratory and EBI) TIGR - The Institute for Genomic Research Gramene - A Comparative Mapping Resource for Monocots Compugen (with its Internet Research Engine) The Zebrafish Information Network (ZFIN) - reference datasets and information on Danio rerio