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DNA/Protein structure-function analysis and prediction

DNA/Protein structure-function analysis and prediction. Basics of Protein Structure: Short Introduction to Molecular Structures “Introduction to Protein Structure” Chapters 1 to 5 Carl Branden & John Tooze ISBN: 0-8153-2305-0 (recommended).

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DNA/Protein structure-function analysis and prediction

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  1. DNA/Protein structure-function analysis and prediction • Basics of Protein Structure: • Short Introduction to Molecular Structures • “Introduction to Protein Structure” • Chapters 1 to 5 • Carl Branden & John ToozeISBN: 0-8153-2305-0 (recommended)

  2. DNA/Protein structure-function analysis and prediction • Basics of Protein Structure: • The building blocks (Ch. 1) • Motifs of protein structure (Ch. 2) • Alpha domain structures (Ch. 3) • Alpha/Beta structures (Ch. 4) • Beta structures (Ch. 5)

  3. Prelude: molecular structures • John Dalton (1810)A new system of chemistry • Elements, but no structures yet • Mendeljev (1869)

  4. Johannes van ’t Hoff • Chimie dans l’Espace“Proposal for the development of three-dimensional chemical structural formulae” (1875) • Tetraedrical carbon atom

  5. Linus Pauling (1951) • Atomic Coordinates and Structure Factors for Two Helical Configurations of Polypeptide Chains • Alpha-helix

  6. James Watson & Francis Crick (1953) • Molecular structure of nucleic acids

  7. James Watson & Francis Crick (1953) • Molecular structure of nucleic acids

  8. DNA/Protein structure-function analysis and prediction • Basics of Protein Structure: • The building blocks (Ch. 1) • Motifs of protein structure (Ch. 2) • Alpha domain structures (Ch. 3) • Alpha/Beta structures (Ch. 4) • Beta structures (Ch. 5) Chains of aminoacids Three-dimensional Structures Four levels of protein architecture Aminoacids: classes Disulphide bridges Histidine Proline Ramachandran plot

  9. The Building Blocks (proteins) • Proteins consist of chains of aminoacids • Bound together through the peptide bond • Special folding of the chain yields structure • Structure determines the function

  10. Chains of aminoacids

  11. Three-dimensional Structures • Four levels of protein architecture

  12. Aminoacids: klassen • Hydrophobic aminoacids Alanine AlaA Valine ValVPhenylalanine PheF Isoleucine IleILeucine LeuL Proline ProPMethionine MetM • Charged aminoacids Aspartate (-) AspD Glutamate (-) GluE Lysine (+) LysK Arginine (+) ArgR • Polar aminoacids Serine SerS Threonine ThrTTyrosine TyrY Cysteine CysCAsparagine AsnN Glutamine GlnQ Histidine HisH Tryptophane Trp W • Glycine (sidechain is only a hydrogen) Glycine GlyG

  13. Disulphide bridges • Two cysteines can form disulphide bridges • Anchoring of secundary structure elements

  14. Ramachandran plot • Only certain combinations of values of phi (f)and psi (y)angles are observed psi psi phi omega phi

  15. DNA/Protein structure-function analysis and prediction • Basics of Protein Structure: • The building blocks (Ch. 1) • Motifs of protein structure (Ch. 2) • Alpha domain structures (Ch. 3) • Alpha/Beta structures (Ch. 4) • Beta structures (Ch. 5) Secundary structure elements Renderings of proteins Alpha helix Beta-strands & sheets Turns and motifs Domains formed by motifs

  16. Motifs of protein structure • Global structural characteristics: • Outside hydrophylic, inside hydrophobic (unless…) • Often globular form (unless…) Artymiuk et al, Structure of Hen Egg White Lysozyme (1981)

  17. Secundary structure elements Alpha-helix Beta-strand

  18. Renderings of proteins • Irving Geis:

  19. Renderings of proteins • Jane Richardson:

  20. Alpha helix • Hydrogen bond: from N-H at position n, to C=O at position n-4 (‘n-n+4’)

  21. Other helices • Alternative helices are also possible • 310-helix: hydrogen bond from N-H at position n, to C=O at position n-3 • Bigger chance of bad contacts • a-helix: hydrogen bond from N-H at position n, to C=O at position n-4 • p-helix: hydrogen bond from N-H at position n, to C=O at position n-5 • structure more open: no contacts • Hollow in the middle too small for e.g. water • At the edge of the Ramachandran plot

  22. Helices • Backbone hydrogenbridges form the structure • Directed through hydrophobic center of protein • Sidechains point outwards • Possibly: one side hydrophobic, one side hydrophylic

  23. Beta-strands: beta-sheets • Beta-strands next to each other form hydrogen bridges

  24. Parallel or Antiparallel sheets Anti-parallel Parallel • Usually only parallel or anti-parallel • Occasionally mixed • Sidechains alternating

  25. Turns and motifs • Between the secundary structure elements are loops • Very short loops between twee b-strands: turn • Different secundary structure elementen often appear together: motifs • Helix-turn-helix • Calcium binding motif • Hairpin • Greek key motif • b-a-b-motif

  26. Helix-turn-helix motif • Helix-turn-helix important for DNA recognition by proteins • EF-hand: calcium binding motif

  27. Hairpin / Greek key motif • Different possible hairpins : type I/II • Greek key:anti-parallel beta-sheets

  28. b-a-b motif • Most common way to obtain parallel b-sheets • Usually the motif is ‘right-handed’

  29. Domains formed by motifs • Within protein different domains can be identified • For example: • ligand binding domain • DNA binding domain • Catalytic domain • Domains are built from motifs of secundary structure elements

  30. Summary • Aminoacids form polypeptide chains • Chains fold into three-dimensional structure • Specific backbone angles are permitted or not:Ramachandran plot • Secundary structure elements: a-helix, b-sheet • Common structural motifs:Helix-turn-helix, Calcium binding motif, Hairpin, Greek key motif, b-a-b-motif • Combination of elements and motifs: tertiary structure • Many protein structures available: PDB

  31. Pauze

  32. DNA/Protein structure-function analysis and prediction • Basics of Protein Structure: • The building blocks (Ch. 1) • Motifs of protein structure (Ch. 2) • Alpha domain structures (Ch. 3) • Alpha/Beta structures (Ch. 4) • Beta structures (Ch. 5) Coiled coil Four helix bundle Globin fold

  33. a-domains • Common a-domains Coiled coil Four helix bundle Globin fold

  34. Coiled coil • Two helices twisted around each other • residues per turn 3.6  3.5 • heptad repeat a-b-c-d-e-f-g • hydrophobic center lined with ionic interactions

  35. Coiled coil: knobs in holes • backbone of two helices parallel • put ‘d’ residues side by side • residues ‘a’ and ‘d’ of helix 1 fit into hollows in helix 2 • results in ~18 degree angle (calculate!)

  36. Four helix bundle • hydrophobic residues packed close together • sequential helices against each other • sometimes two coiled coils: knobs-in-holes

  37. Four helix bundle: ridges in grooves • Group aminoacids and recognize lines • Fit these lines onto each other • results in 60 or 20 degree angle (calculate) • Depends strongly on helical parameters n,n+4 n,n+3

  38. Globin fold • Common theme • 8 helices (ABCDEFGH), short loops • Still much variation (16 – 99 % similarity) • Helix length • Exact position • Shift through the ridges

  39. DNA/Protein structure-function analysis and prediction • Basics of Protein Structure: • The building blocks (Ch. 1) • Motifs of protein structure (Ch. 2) • Alpha domain structures (Ch. 3) • Alpha/Beta structures (Ch. 4) • Beta structures (Ch. 5) Different a-b-a groups Alpha/beta barrels Horseshoe fold Twisted open-sheet structures Predicting location of active site

  40. Alpha/beta structures Barrel Open twisted sheet Horseshoe fold

  41. Different a-b-a groups barrels / horseshoe open twisted sheet

  42. Alpha/beta barrels • TIM barrel after triosephosphate isomerase • Usually 8 b-strands, at least 200 aminoacids • Often hydrophobic interior • alternating aminoacids in the strands

  43. Alpha/beta barrels • Active site formed by (variable) loop regions at top of the barrel • Exception:in the core of methylmalonyl-coenzyme A mutase

  44. Horseshoe fold • Repetetive sequenties (20 aminoacids) • Leucine-containing • Found in about 60 proteins

  45. Twisted open-sheet structures • Helices at both sides of the sheet • Active site is usually found at junction of the sheet • Much variation in structures

  46. Predicting location of active site • When sequence of the strands is broken, usually a crevice, which often contains the active site

  47. DNA/Protein structure-function analysis and prediction • Basics of Protein Structure: • The building blocks (Ch. 1) • Motifs of protein structure (Ch. 2) • Alpha domain structures (Ch. 3) • Alpha/Beta structures (Ch. 4) • Beta structures (Ch. 5) Up-and-down barrels Greek key barrels Jelly-roll barrels Propeller structures Beta-helices Compare parallel sheets

  48. Beta structures • barrels • up-and-down barrels • greek key barrels • jelly roll barrels • propeller like structure • beta helix

  49. Up-and-down barrels • Relatively simple structure • Aminoacids alternating hydrophobic / hydrophilic • inside – outside • Example retinol binding protein • But also OmpX • P2 family: 10 strands

  50. Greek key barrels • Greek key motif occurs also in barrels • two greek keys (g crystallin) • combination greek key / up-and-down

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