The Jena Library of Biological Macromolecules – JenaLib (fli-leibniz.de/IMAGE.html)

1. The Jena Library of Biological Macromolecules – JenaLib (www.fli-leibniz.de/IMAGE.html) Jürgen Sühnel jsuehnel@fli-leibniz.de Biocomputing Group Leibniz Institute for Age Research, Fritz Lipmann Institute, Jena Centre for Bioinformatics Jena / Germany (November 2006)

2. Related information: Lecture Series ‚3D Structures of Biological Macromolecules‘ http://www.fli-leibniz.de/www_bioc/3D/

3. Fritz Lipmann The Journal of Biological Chemistry 186, 235, 1950

4. Coenzyme A

5. Biocomputing Group: Research and Service • Identification and Analysis of Unusual Structural Motifs in Proteins and • Nucleic Acids • Water-Mediated Base Pairs • Base Polyad Motifs in DNA Mutiplex Structures • C-H...O/N Interactions in RNA Structures • C-H... Interactions in Proteins(IMB, X-Ray Crystallography: Weiss) • Nest Motifs and Non-repetitive Dipeptide Patterns in Proteins • (UCLA: Pal; EMBL Hamburg Outstation: Weiss) • Database ‚Jena Library of Biological Macromolecules (JenaLib)‘ • Computational Genomics of Prokaryotes(IMB/FLI Genome Analysis Group: Platzer) • Short-term Collaborative Projects • Structure and Conformational Analysis of Ampullosporin A • (HKI: Gräfe; • Friedrich Schiller University: Görls, Reissmann) • Computer Selection of DNA Oligonucleotide Probe Combinations for COMBO-FISH • (Heidelberg/Freiburg University: Hausmann) • Chromatin Structure (FLI, Molecular Biology Group: Diekmann) • Websites for Molecular Biology • The RNA World Website • The JCB Protein-Protein Interaction Website • Maintenance of the Institutional Computer Network Computational Structural Biology Computational Genomics Other Service www.fli-leibniz.de/www_bioc/

6. Biocomputing Group: Databases, Websites/Webtools • The Jena Library of Biological Macromolecules (JenaLib) www.fli-leibniz.de/IMAGE.html • The RNA World Website www.fli-leibniz.de/RNA.html • The JCB Protein-Protein Interaction Website www.fli-leibniz.de/jcb/ • The Jena Prokaryotic Genome Viewer jpgv.fli-leibniz.de • The Spirochetes Genome Browser sgb.fli-leibniz.de

7. Biocomputing Group: Methods • Quantum Chemistry • Molecular Dynamics • (Structural) Bioinformatics • Computational Genomics • Database / Website Development

8. DNA Structure: History

9. DNA Structure: History

10. DNA Structure: Ideal B-DNA Conformation

11. First Single-Crystal DNA Structure (B-DNA) Drew-Dickerson structure H. R. Drew, R. M. Wing, T. Takano, C. Broka, S. Tanaka, K. Itakura, R. E. Dickerson Structure Of A B-/DNA Dodecamer. Conformation And Dynamics Proc. Nat. Acad. Sci. Usa V. 78 2179 1981

12. Protein Structure: The Protein -Helix • The first and still one of the greatest triumphs of speculative model building in structural chemistry/biology • Forerunner of computer-assisted • model building In the PNAS paper the helix is drawn left-handed !!!!! Linus Pauling and Robert Corey with a wooden model of a protein -helix (1 inch per Å) Pauling, Corey, Branson. The structure of proteins: Two hydrogen-bonded helical conformations of the polypeptide chain. Proc. Natl. Acad. USA1951, 37, 205-211.

13. Protein Structure: Hemoglobin Model www2.mrc-lmb.cam.ac.uk/archive/Perutz62.html

14. The Oldest Myoglobin and Hemoglobin Structures in the PDB Myoglobin (1mbn) Hemoglobin (2dhb) 2 alpha chains: 146 aa (green, cyan) 2 beta chains: 141 aa (red, brown) (Watson, Kendrew: 1973) (Perutz et al.: 1973)

15. Myoglobin Model Built by A. A. Barker, Model Maker in Cambridge (UK) www.umass.edu/molvis/francoeur/barker/barker.html

16. Protein Structure: History

17. Nobel Prizes for Both DNA and Protein Structures

18. Structural Biology Nobel Prices

19. Protein Structure: Thermodynamic Hypothesis Christian B. Anfinsen The native structure of a protein corresponds to the minimum of free energy.

22. Protein Structure: Amino Acids

23. Protein Structure: Amino Acids www.fli-leibniz.de/IMAGE_AA.html

24. Internal Co-ordinates (Bond) Distance [2 atoms] (Bond) Angle [3 atoms] Torsion angle [4 atoms] C D B A

25. Protein Structure Sequence Protein-protein or protein-nucleic acid complexes Secondary structure elements Domains/Folds/Chains

26. Protein Structure: Secondary Structure Elements

27. Protein Structure: The Protein -Helix • The first and still one of the greatest triumphs of speculative model building in structural chemistry/biology • Forerunner of computer-assisted • model building In the PNAS paper the helix is drawn left-handed !!!!! Linus Pauling and Robert Corey with a wooden model of a protein -helix (1 inch per Å) Pauling, Corey, Branson. The structure of proteins: Two hydrogen-bonded helical conformations of the polypeptide chain. Proc. Natl. Acad. USA1951, 37, 205-211.

28. Protein Structure: Domains Structure-based definition Dali Fold Classification Sequence-based definition

29. Protein Domains: JenaLib Jmol Viewer calcium-free human calpain Calpains (calcium-dependent cytoplasmic cysteine proteinases) are implicated in processes such as cytoskeleton remodeling and signal transduction.

30. Protein Domains: JenaLib Jmol Viewer

31. Protein Structure: Backbone Torsion Angles D. W. Mount: Bioinformatics, Cold Spring Harbor Laboratory Press, 2001.

32. Protein Structure: The Ramachandran Map Theoretical Beta-sheet Left-handed alpha-helix Right-handed alpha-helix Ramachandran, Ramakrishnan, Sasisekharan. Stereochemistry and polypeptide chain configurations. J. Mol. Biol. 1963, 7, 95-99. Ramachandran, Sasisekheran. Conformation of polypeptides and proteins. Adv. Protein. Chem.1968, 23, 283-438. non-glycines glycines Experimental 237 384 amino acids in 1041 protein chains Hovmöller et al., Acta Cryst. D2002, 58, 768-776

33. PDB Growth Rate 2005: ~ 15 new structures per day

34. Motivation There is an insufficient impact of the available 3D structural information on biopolymers outside structural biology. 1993  IMB Jena Image Library of Biological Macromolecules • Visualization and other analysis tools for complete structures and structure parts • Classification • Extensive cross-referencing • As much information as possible in one place • Editorial, Nature Struct. Biol.1997, 4, 329-330. • Structure and the genome • “rift between the sequence and the structure world” • “clash of scientific cultures and the inherent complexity of structure • data” • “even experienced sequence analysts can sort of get ill when they look • at a coordinate file” • “What do molecular biologists fear most? Three letters: PDB.” Related attempt at that time  Swiss-3D-Image 1992: 1006 PDB entries 2004: 29841 PDB entries

35. Mission and Features The IMB Jena Image Library of Biological Macromolecules is aimed at a better dissemination of information on three-dimensional biopolymer structures with an emphasis on visualization and analysis. It provides access to all structure entries deposited at the Protein Data Bank (PDB) or at the Nucleic Acid Database (NDB). In addition, basic information on the architecture of biopolymer structures is available. The IMB Jena Image Library intends to fulfill both scientific and educational needs. • Basic information on the architecture of biopolymers • Atlas pages for all entries with as much information as possible in one place • Various visualization tools for complete structures and structure parts including a • user-friendly SCOP domain viewer and both raster and vector graphics output • Hetero components database • Site database • Environment analysis of hetero components and sites • Species classification including a PDB structures species timeline • Gene Ontology classification of PDB structures • Comprehensive bending classification of nucleic acid double helix structures • Versatile search options allowing the direct search for identifiers/names from • PDB, NDB, UniProt, Pfam, SMART, SCOP, GO • Links to more than 30 external databases • ………….

36. RNABase Cross references from other databases Systers ~ 1 information request per minute Reichert, Sühnel. The IMB Jena Image Library of Biological Macromolecules - 2002 update. Nucleic Acids Res.2002, 30, 253-254. Bioinformatics Group (K. Schmid)

37. Different Protein Views Structural Biology Genomics Porin (1a0s) Cell Biology Systems Biology SIR2p – NAD+-dependent histone deacetylase PNC1 – pyrazinamidase/nicotinamidase

38. Gallery

39. Start Page

40. Start Page

41. Atlas Page

42. Atlas Page

43. UniProt/PDB Alignment Viewer Bioinformatics Group (K. Schmid)

44. UniProt/PDB Alignment Viewer Bioinformatics Group (K. Schmid)

45. UniProt/PDB Alignment Viewer Bioinformatics Group (K. Schmid)

46. Integrated Viewing Bioinformatics Group (K. Schmid) JenaLib Jmol Viewer (jmol.sourceforge.net)

47. Chain A of the structure of the human alcohol beta 1 dehydrogenase (Protein Data Bank code: 1DEH) is shown in the viewer. The structure consists of the N-terminal (red) and C-terminal (blue) alcohol dehydro-genase SCOP domains. In addition, the following structural features are shown: - ligands (4-iodopyrazole, NAD; spacefilling representation), - Zn-containing active sites, - PROSITE motif (thick trace, tomato-colored), - SAPs from UniProtKB (wt – magenta, mutated – cyan). VAR_000426 is assumed to be associated with a lower risk of alcoholism. Note, that both the SAPs and the PROSITE motif occur in the (red) N-terminal SCOP domain. Bioinformatics Group (K. Schmid)

48. A Structural Understanding of Friedreich‘s Ataxia Frataxin SNP/SAP mutations in frataxin are associated with Friedreich´s ataxia (FRDA), a recessive neurodegenerative disorder that involves progressive loss of voluntary muscular coordination and heart enlargement and can lead to death. It is assumed that the condition arises from disregulation of mitochondrial iron homeostasis with concomitant oxidative damage leading to neuronal death (OMIM : 229300). Ile 154 Arg is the most common mutation and leads to a severe phenotypein several independent families. Trp 165 Arg involves an absolutely conserved Trp. G. Musco et. al., Structure 8 (2000), 695

49. A Structural Understanding of Friedreich‘s Ataxia JenaLib Jmol Viewer Frataxin TRP155->ARG is exposed and replaces an aromatic by a positively charged sidechain. ILE154->PHE is buried but located at the interface between different secondary structure elements. Here a smaller sidechain is replaced by a larger one.

50. A Structural Understanding of Friedreich‘s Ataxia JenaLib Jmol Viewer Frataxin TRP155->ARG [W155R] ILE154->PHE [I154F] TRP155->ARG is exposed and replaces an aromatic by a positively charged sidechain. ILE154->PHE is buried but located at the interface between different secondary structure elements. Here a smaller sidechain is replaced by a larger one.