Protein Secondary Structure

1. Protein Secondary Structure

2. 1958: Kendrew Solves the Structure of Myoglobin “Perhaps the most remarkable features of the molecule are its complexity and its lack of symmetry. The arrangement seems to be almost totally lacking in the kind of regularities which one instinctively anticipates, and is more complicated than has been predicted by any theory of protein structure”

3. Protein Secondary Structure Protein interior: Hydrophobic core Main chain folds also into interior, but it is highly polar →Problem: Polar atoms must be neutralized through hydrogen bonds →Solution: Regular secondary structure

4. a Helix • Discovered 1951 by Pauling • 5-40 aa long • Average: 10aa • Right handed • Oi-NHi+4 : bb • atoms satisfied • p helix: i - i+5 • 310 helix: i - i+3 1.5Ǻ/res

5. a Helix is a Dipole … and binds negative charges at N-term

6. Side Chains project out from the Helix View down one helical turn

7. CO N C H H2C CH2 CH2 Proline Disrupts Helix No donor!

8. Frequent Amino Acids at the N-terminus of a helices Ncap, N1, N2, N3 …….Ccap Pro Blocks the continuation of the helix by its side chain Asn, Ser Block the continuation of the helix by hydrogen bonding with the donor (NH) of N3

9. Helices of Different Character Buried, partially exposed, and exposed

10. Representation: Helical Wheel Buried, partially exposed, and exposed

11. Dihedral Angles F and  define Backbone Geometry  F w The peptide bond w is planar and polar

12. Ramachandran Plots  F All except Glycine Glycine: flexible backbone

13. Ramachandran Plots  F • helix: F,  around -60,-50, respectively Other defined regions: b strand and loops

14. b-Sheet • Involves several regions in sequence • Oi-NHj • Parallel and • anti-parallel • sheets

15. Antiparallel b-Sheet • Parallel Hbonds • Residue side chains point up/down/up .. • Pleated

16. Parallel b-Sheet • Less stable than antiparallel sheet • Angled • hbonds

17. Combined b-Sheet Rare: strains in middle strand

18. Examples of b-Sheet Topologies Topology diagram Closed barrel

19. Connecting Elements of Secondary Structure defines Tertiary Structure

20. Loops • Connect helices and strands • At surface of molecule • More flexible • Contain functional sites

21. Hairpin Loops (b turns) • Connect strands in antiparallel sheet G,N,D G G S,T

22. Super Secondary Structures: (1) Greek Key Motif • 24 possible topologies for 2 hairpins • 8 found • Most common: Greek key motif

23. Super Secondary Structures: (2) b-a-b Motif • Connect strands in parallel sheet

24. Repeated b-a-b Motif Creates b-meander: TIM Barrel

25. Large Polypeptide Chains Fold into Several Domains

26. Protein Classification

27. Protein Classification Alpha contain only a helices Beta contain only b sheets Alpha/Beta contain combination of both Alpha + Beta contain domains of a and b

28. ALPHA • Occur in • Transmembrane proteins • Structural and motile proteins • Fibrous proteins (Keratin) • Fibrinogen, myosin • Coiled-coils (Leucine Zippers) • 4-helix-bundles • a-helical domains • Globins

29. ALPHA: Coiled-Coils • Francis Crick, 1953: maximal sc interactions if two helices are wound around each other • Left-handed supercoil: 3.5 residues/turn: • Heptad repeat • “knobs-into-holes” • Leucine zipper motif in Transcription Factors (more about this later..)

30. ALPHA: 4-Helix Bundle • “ridges-into-grooves” ROP protein

31. Ridges-into-Grooves • 2 possible arrangements: • i-i+4 ridge: • Globins • i-i+3 ridge: • ROP

32. ALPHA: a-Helical Domains • >20 a helices form globular domain • Example: muramidase • 27 helices • right-handed • superhelical twist • Hole in center

33. ALPHA/BETA • Most frequent • 3 classes: • Barrel • Twisted sheet • Horseshoe fold • Functional sites in loop regions

34. ALPHA/BETA: Barrels • Consecutive a-b-a units • in same orientation • Usually 8; b8-hb- b1 • → closed core of b strands • TIM barrel • Triose Phosphate Isomerase • Usually enzymes

35. TIM Barrels • aa2,4 point out to helices • branched aasV,I,L • aa1, 3, 5 point into barrel • Bulky hydrophobic aas form tightly packed hydrophobic core • Polar aas (KRE) at tip of barrel: participate in formation of hydrophobic core

36. TIM Barrels Active site formed by loops at one end of the barrel Distinct from structural region

37. ALPHA/BETA: Open Sheet • Consecutive a-b-a units • in opposite orientation: • helices on both sides • Rossman Fold • (discovered in 1970 in lactate dehydrogenase) • Many different arrangements

38. Open Sheet: Functional Sites at Topological Switch Points

39. ALPHA/BETA: Horseshoe Fold • Consecutive a-b-a units in same orientation • Not closed: horseshoe • Ribonuclease • Inhibitor • One side points to helix, • The other is exposed

40. Horseshoe Fold • Leucine-rich repeats • each ~30aa • L responsible for packing

41. BETA Antiparallel b structures Usually two sheets packed against each other Barrel: composed of anti-parallel strands with hairpin connections Propeller: multi-domain protein

42. BETA Barrels Retinol-binding protein 8 strands Center: hydrophobic pocket binds lipids

43. BETA Propellors (I) • Neuraminidase • 6 b-sheets (each 4 strands) organized as propellor blades • Active site formed by loops from each blade • Others: G-proteins, etc

44. BETA Propellors (II) • Neuraminidase • 6 b-sheets(each 4 strands)organized as propellor blades • Active site formed by loops from each blade

45. BETA Propellors (III) • Neuraminidase • 6 b-sheets (each 4 strands) organized as propellor blades • Active site formed by loops from each blade

46. BETA: Jelly-Roll MotifWrapped around a Barrel Composed of repeats of greek keys Concavalin, Hemagglutinin

47. BETA: b-helix Structures Right-handed coiled structure 18aa: 6 in loop+ 3 in b GGXGXDXUX (U=hydrophobic) Loop stabilized by Ca ion Pectate lyase

48. Additional Useful Material http://swissmodel.expasy.org/course/text/