1. Bioinformatics Ch1. Introduction (continue-2) 阮雪芬 Nov7, 2002 NTUST www.ntut.edu.tw/~yukijuan/lectures/bioinfo/Nov7.ppt

2. Searching for Similar Sequences in Databases: PSI-BLAST Determine the sequence of a new gene Identify within the human genome a gene responsible for some disease To determine whether related genes appear in other species The ideal method is 1.Sensitive 2.Selective

3. Searching for Similar Sequences in Databases: PSI-BLAST  A powerful tool for searching sequence databases with a probe sequence is PSI- BLAST  BLAST: An earlier program worked by identifying local regions of similarity without gaps and then piecing them together.  PSI-BLAST: refer to enhancements that identify patterns within the sequences at preliminary stages of the database search, and then progressively refine them.

4. Ex. 1.4 P26367

5. Ex. 1.4 PAX-6

6. Ex. 1.4 Sequence PSI- and PHI-BLAST http://www.ncbi.nlm.nih.gov/blast/index.html

7. Ex. 1.4 gi|1352719|sp|P47237|PAX6_CHICK Paired box protein Pax-6 379 e-105 gi|1352719|sp|P47237|PAX6_CHICK379

8. Ex. 1.4

9. EX.1.5  What species contain homologues of human PAX-6 detectable by PSI- BLAST?

10. EX.1.5

13. Introduction to Protein Structure  Protein Function: Structural proteins Catalyse chemical reactions Transport and storage proteins Regulatory proteins  Hormones  Receptor/signal transduction proteins Control genetic transcription Protein involved in recognition  cell adhesion molecules  Antibodies and other proteins of the immune system

14. Primary Structure

15. Peptide-bond Formation

16. Amino Acid Sequences Have Direction

17. Components of a Polypeptide Chain Backbone: constant Side chains: variable

18. Introduction to Protein Structure  Proteins are large molecules (backbone)

19. Secondary Structure  -helix -sheet

20. Supersecondary structure  -helix hairpin  -helix hairpin   unit

21. Domains  Many proteins contain compact units within the folding pattern of a single chain, that look as if they should have independent stability. The cell-surface protein CD4 consists of four similar domains

22. Modular proteins  Modular proteins are multidomain proteins which often contain many copies of closely related domain.  Fibronectin: a large extracellular protein involved in cell adhesion and migration contains 29 domains including multiple tandem repeats of three typesof domains called F1, F2 and F3

23. http://www.bork.embl-heidelberg.de/Modules/07-matrix.gif

24. Classification of Protein Structure  Occupies a key position in bioinformatics, not least as a bridge between sequence and function

25. Divide the Proteins into Domains

26. Protein Structure Prediction and Engineering  Secondary structure prediction  Fold recognition  Homology modelling

27. Protein Structure Prediction and Engineering  Critical Assessment of Structure Prediction (CASP)  Protein engineering

28. Clinical Implications  Categories of applications Diagnosis of disease and disease risks Genetics of responses to therapy Identification of drug targets Gene therapy

29. Diagnosis of Disease and Disease Risks  DNA sequencing can detect the absence of a particular gene, or a mutation  Identification of specific gene sequences associated with disease  In many cases our genes do not irrevocably condemn us to contract a disease, but raise the probability that we will. 1-antitrypsin: inhibit elastase in the alveoli of the lung A combination of genetic and environmental factors

30. Genetics of Responses to Therapy  Customized treatment  Sequence analysis permits selecting drugs and dosages optimal for individual patients--- pharmacogenomics  The very toxic drug 6-mercaptopurine is used in the treatment of childhood leukaemia Lack Thiopurine methyltransferase Die

31. Identification of Drug Targets  A target is a protein the function of which can be selectively modified by interaction by a drug, to affect the symptoms or underlying causes of a diease.

32. Gene Therapy  A gene is missing or defective  replace it  A gene is overactive  turn it off