1. Protein Structure and Energetics
Adam Liwo
Room B325
Faculty of Chemistry, University of Gdańsk
phone: (or 5124 within the University)
Course language: English

2. Schedule and requirements
Mondays, 8:15 – 10:00, room C209, Faculty of Chemistry, University of Gdańsk
2 problem sets
Final exam

3. Scope of this course Levels of structural organization of proteins.
Quantitative description of protein geometry.
Secondary and supersecondary structure.
Tertiary and quaternary structure.
Schemes of protein-structure classification.
Interactions in proteins and their interplay.
Folding transition as a phase transition.
Foldability and the necessary conditions for foldability.
Misfolding and aggregation; formation of amyloids.
Experimental methods for the investigation of protein folding.
Atomistic-detailed and coarse-grained models and force fields for protein simulations.

4. Literature
C. Branden, J. Toze, „Introduction to Proten Structure”, Garland Publishing,1999
G. E. Schultz, R.H., Schrimer, „Principles of Protein Structure”, Springer-Verlag, 1978
Ed. J. Twardowski, „Biospektroskopia”, cz. I, PWN, 1989
I. Z. Siemion, „Biostereochemia”, PWN, 1985

5. Proteins: history of view
1828: By syntesizing urea, Friedrich Woehler voided the vis vitalis theory, opening roads to modern organic chemistry.
1850’s: First amino acids isolated from natural products
: By hydrolysis of natural proteins, Emil Fischer proves that they are copolymers of amino acids (strange, but none of his so fundamental papers earned more than ~60 citations!).
1930’s and 1940’s: proteins are viewed as spheroidal particles which form colloidal solution; their shape is described in terms of the long-to-short axis ratio.
1930’s: it is observed that denaturated proteins do not crystallize and change their physicochemical and spectral properties.

6. Proteins: history of view (continued)
1940’s: evidence from X-ray accumulates suggesting that fibrous proteins such as silk and keratin might have regular structure.
1951: Pauling, Corey, and Branson publish the theoretical model of protein helical structures.
1960: Laskowski and Scheraga discover anomalous pKa values in ribonuclease, which suggest that the acidbase groups are shielded from the solvent to different extent.
1963: First low-resolution X-ray structure of a protein (horse hemoglobin) published by the Perutz group.
Today: structures of proteins, nucleic acids, and sugars in the Protein Data Bank.

7. Protein shapes from viscosity datab
Polson, Nature, 740, 1936

8. Pauling’s model of helical structures

10. First structure: hemoglobin (X-ray)

12. Example of a recently solved structure: DnaK chaperone from E
Example of a recently solved structure: DnaK chaperone from E.coli (2KHO)

13. Levels of protein structure organization

14. The primary structure (Emil Fischer, 1904)
C-terminus
N-terminus
H3N+-Gly-Ile-Val-Cys-Glu-Gln Thr-Leu-His-Lys-Asn-COO-
a-amino acids are protein building blocks

15. a-amino acids: chemical structure

16. Classification of amino-acids by origin
Natural
Synthetic
Proteinic (L only)
Non-Proteinic (D and L)
Primary (coded)
Secondary (post-translational modification)
Tertiary (e.g., cystine)
Endogenous
Exogenous

17. Amino-acid names and codes
Synthesized in humans
Supplied with food
Name
Code
Alanine
Ala A
Histidine
His H
Arginine
Arg R
Isoleucine
Ile I
Asparagine
Asn N
Leucine
Leu L
Aspartic acid
Asp D
Lysine
Lys K
Cysteine
Cys C
Methionine
Met M
Glutamine
Gln Q
Phenylalanine
Phe F
Glutamic acid
Glu E
Threonine
Thr T
Glycine
Gly G
Tryptophan
Trp W
Proline
Pro P
Valine
Val V
Serine
Ser S
Tyrosine
Tyr Y

18. The peptide bond

22. Venn diagram of amino acid properties

23. The "Universal" Genetic Code In form of codon, Left-Top-Right (ATG is Met)
Phe
Ser
Tyr
Cys
Leu
Ter
Trp
Pro
His
Arg
Gln
Ile
Thr
Asn
Lys
Met
Val
Ala
Asp
Gly
Glu

24. Atom symbols and numbering in amino acids

25. Chirality Enantiomers
Phenomenological manifestation of chiraliy: optical dichroism (rotation of the plane of polarized light).

26. Determining chirality
Highest oxidation state
Chain direction

27. The CORN rule

28. Absolute configuration: R and S chirality
Rotate from „heaviest” to „lightest” substituent
R (D) amino acids
S (L) amino acids

29. Representation of geometry of molecular systems
Cartesian coordinates
describe absolute geometry of a system,
versatile with MD/minimizing energy,
need a molecular graphics program to visualize.
Internal coordinates
describe local geometry of an atom wrt a selected reference frame,
with some experience, local geometry can be imagined without a molecular graphics software,
might cause problems when doing MD/minimizing energy (curvilinear space).

30. Cartesian coordinate systemz
Atom x (Å) y (Å) z (Å)
C(1)
O(2)
H(3)
H(4)
H(5)
H(6)
zH(6)
H(6)
O(2)
H(4)
C(1)
yH(6)
xH(6) x
H(5) y
H(3)

31. Internal coordinate system
i dij aijk bijkl j k l
C(1)
O(2) *
H(3) * *
H(4) * * *
H(5) * * *
H(6) * * *
H(6)
O(2)
H(4)
C(1)
H(5)
H(3)

32. Bond length

33. Bond (valence) angle

34. Dihedral (torsional) angle
The C-O-H plane is rotated counterclockwise about the C-O bond from the H-C-O plane.

35. Improper dihedral (torsional) angle

36. Bond length calculationzj zi xi yi xj xj

37. Bond angle calculationj
aijk i k

38. Dihedral angle calculation
bijkl k j l

39. The vector product of two vectorsq

41. Some useful vector identities

42. i
aijk
180o-aijk k j

43. i
bijkl k j l

44. bijkl k j l

45. Calculation of Cartesian coordinates in a local reference frame from internal coordinates
H(5) z
H(6)
d26
C(1)
a426
H(3)
b3426
O(2) y x
H(4)

46. Need to bring the coordinates to the global coordinate system

47. Polymer chains pi-1 qi+2 qi+2 wi+1 qi+1 wi+1 i+1 i+1 di+1 di+1 i i di

48. For regular polymers (when there are „blocks” inside such as in the right picture, pi is a full translation vector and Ti-2Ri-1 is a full transformation matrix).

49. Hybrid of two canonical structures
Peptide bond geometry
Hybrid of two canonical structures
60% 40%

50. Electronic structure of peptide bond

51. Peptide bond: planarity
The partially double character of the peptide bond results in
planarity of peptide groups
their relatively large dipole moment

52. Main chain conformation: the f, y, and w angles
The cis (w=0o) and trans (w=180o) configurations of the peptide group

53. Peptide group: cis-trans isomerization
Skan z wykresem energii

54. Because of peptide group planarity, main chain conformation is effectively defined by the f and y angles.

55. Side chain conformations: the c angles

56. The dihedral angles with which to describe the geometry of disulfide bridges

57. Some  and  pairs are not allowed due to steric overlap (e.g, ==0o)

58. The Ramachandran map