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Sequence-Structure-Function

Sequence-Structure-Function. Sequence Structure Function. Folding: impossible but for the smallest structures. Ab initio. Threading. Function prediction from structure – very difficult. BLAST. Experimental. Structural genomics Functional genomics Protein-protein interaction

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Sequence-Structure-Function

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

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

  3. 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)

  4. 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)

  5. 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

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

  7. Protein function evolution Chymotrypsin

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

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

  10. Metabolic networksGlycolysis and Gluconeogenesis Kegg database (Japan)

  11. 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

  12. The GO ontology

  13. Gene Ontology Members

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