Protein Structure and Energetics

1. Adam Liwo Room 406 Faculty of Chemistry, University of Gdańsk phone: 58 345 5430 (or 5430 within the University) email: adam@chem.univ.gda.pl Protein Structure and Energetics Course language: English

2. Schedule and requirements • Thursdays, 8:15 – 10:00, room 330, Faculty of Chemistry, University of Gdańsk • 2 problem sets • Final exam

3. Scope of this course • Levels of structuralorganization of proteins. • Quantitative description of protein geometry. • Secondary and supersecondary structure. • Tertiary and quaternary structure. • Schemesof 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 forprotein 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 smashes the vis vitalis theory, opening roads to modern organic chemistry. • 1850’s: First amino acids isolated from natural products • 1903-1906: 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: 68840 structures of proteins, nucleic acids, and sugars in the Protein Data Bank.

7. Protein shapes from viscosity data a b 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.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 Amino acids Natural Synthetic Proteinic (L only) Non-Proteinic (D and L) Primary (coded) Secondary (post-translationalmodification) Tertiary (e.g., cystine) Endogenous Exogenous

17. Amino-acid names and codes

18. The peptide bond

22. Venn diagram of amino acid properties

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

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 S (L) amino acids R (D) amino acids

29. Representation of geometry of molecular systems • Cartesiancoordinates • describeabsolute geometry of a system, • versatilewith MD/minimizing energy, • need a moleculargraphics program to visualize. • Internalcoordinates • describelocal geometry of an atom wrt a selectedreferenceframe, • withsomeexperience, local geometry can be imaginedwithout a moleculargraphics software, • mightcauseproblemswhendoing MD/minimizing energy (curvilinearspace).

30. Cartesian coordinate system z Atom x (Å) y (Å) z (Å) C(1) 0.000000 0.000000 0.000000 O(2) 0.000000 0.000000 1.400000 H(3) 1.026719 0.000000 -0.363000 H(4) -0.513360 -0.889165 -0.363000 H(5) -0.513360 0.889165 -0.363000 H(6) 0.447834 0.775672 1.716667 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 dijaijkbijkl j k l C(1) O(2) 1.40000 * 1 H(3) 1.08900 * 109.47100 * 1 2 H(4) 1.08900 * 109.47100 * 120.00000 * 1 2 3 H(5) 1.08900 * 109.47100 * -120.00000 * 1 2 3 H(6) 0.95000 * 109.47100 * 180.00000 * 2 1 5 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 calculation zj zi xi yi xj xj

37. Bond angle calculation j aijk i k

38. Dihedral angle calculation i bijkl k j l

39. The vector product of two vectors q

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 qi+2 qi+2 wi+1 wi+1 qi+1 i+1 i+1 di+1 di+1 i i di wi pi-1 i-1 wi-1 wi-1 qi-1 qi-1 i-1 di-1 di-1 qi i-2 i-2

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

50. Electronic structure of peptide bond