1. Protein Structure
September 7,

2. Basics of Protein Structure
Primary structure: sequence
Secondary structure:
α-helix, -sheet, -strand, loop
Supersecondary structure, motifs
Tertiary structure:
folding into functional domains with ordered structure composed of secondary structure elements
Quaternary structure
Complexes of monomers to form active structures

3. Amino acid

4. 20 amino acids - the building blocks

5. Amino acid categories Aliphatic
Valine, Alanine, Leucine and Isoleucine
Aromatic
Phenylalanine, Tyrosine and Tryptophan
Charged
Aspartic, Glutamic, Histidine, Lysine, Arginine
Polar
Serine, Threonine, Cysteine, Methionine, Asparagine, Glutamine
Odd couple
Glycine, Proline

6. Aliphatic residues

7. Aromatic Residues

8. Charged Residues
Side-chains are charged under physiological conditions
Acid are negatively charged
Basic are positively charged

9. Polar Residues

10. The Odd Couple

11. Peptide-bond formation

12. Backbone torsion anglesw
f phi y psi
omega 180° trans
0° cis

13. Ramachandran Plot

14. Other chemical bonds Disulfide bonds or bridges
Formed by oxidation of thiol groups of two cysteines
Form a bond about 2Å in length.
Predominant feature in many small proteins
H-bonds not truly covalent
Dipolar attraction between O and H
Complex geometry wrt distances and angles

15. Side Chain Conformation

16. Side Chain Torsion Angles
The side chain torsion angles are named c1(chi1), c2(chi2), c3 (chi3), etc., as shown below for lysine.

18. Hydrophilic or hydrophobic…?
Virtually all soluble proteins feature a hydrophobic core surrounded by a hydrophilic surface
Peptide backbone is inherently polar
Neutralize potential H-donors & acceptors using ordered secondary structure

19. Alpha helix H-bonds between N-H and C=O groups in polypeptide backbone
Compact structure
3.6 residues
Pitch: 5.6Å/turn
Rise: 1.5Å/residue
Polar/hydrophilic residues on 1 face with nonpolar or hydrophobic residues on other face

20. Secondary Structure: -helix
3.6 residues / turn
Axial dipole moment
Not Proline & Glycine
Protein surfaces

22. Beta-sheet Extended structure
Side-chains project alternately up or down
Amphipathic is solvent exposed
polar residues on one side and non-polar on other side

23. Secondary Structure: -sheets

24. Secondary Structure: -sheets
Parallel or antiparallel
Alternating side-chains
No mixing
Loops often have polar amino acids

25. Parallel -sheets:

26. Antiparallel -sheets:

27. Silk fibroin

28. Supersecondary structures
Also called motifs
Simple combinations of secondary structures

29. -hairpins

30. Two-residue -hairpins

31. Three-residue -hairpins

32. -meander

33. corners are observed to have a right-handed twist when viewed from the concave side

34. Helix hairpins

35. The  corner

36. EF hand

37.  motifs

38. Greek Key Motif

39. Tertiary Structure Combinations of motifs to form domains
Three main classes
All alpha
Alpha/beta
All beta

40. Alpha Domain Structures
Four helix bundle
Globin fold

42. Myohemeyrthrin

43. Cytochrome b452

44. Ferritin

45. Globins

46. Packing of helices

48. Alpha/beta
TIM barrel
Rossmann fold
Horseshoe fold

49. TIM Barrel

50. Horseshoe Fold

51. Rossmann Fold

52. All Beta
Up and down barrels
Greek key barrels
Jelly roll barrels

53. Up and down barrel retinol binding protein

54. Greek Key Barrel

55. Jellyroll barrel

56. Beta helix

57. Protein Structure Databases
CATH - Protein Structure Classification
hierarchical classification of protein domain structures
UCL, Janet Thornton & Christine Orengo
clusters proteins at four major levels:
Class(C)
Architecture(A)
Topology(T)
Homologous superfamily (H)
[ ]

58. Class(C) derived from secondary structure content is assigned automatically
Architecture(A) describes the gross orientation of secondary structures, independent of connectivity.
Topology(T) clusters structures according to their topological connections and numbers of secondary structures
[ ]

61. Quaternary Structure

66. Quaternary Structure

67. Quaternary Structure

68. References
"Crystallization, X-ray studies, and site-directed cysteine mutagenesis of the DNA-binding domain of OmpR", E. Martínez-Hackert, S. Harlocker, M. Inouye, H. M. Berman and A. M. Stock, Journal/Protein Sci., 5: , 1996.
(School of Crystallography, Birkbeck, University of London)
(MSD-EBI Roadshow)
"Introduction to protein structure", Brandon and Tooze, 3, 21, 1999.