Secondary and sidechain structures

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1 Lecture 2 Secondary and sidechain structures James Chou BCMP201 Spring 2008

2 Images from Petsko & Ringe, Protein Structure and Function. Branden & Tooze, Introduction to Protein Structure. Richardson, J. S. & Richardson, D. C. Principles and Patterns of Protein Conformation.

3 IUPAC definition of dihedral angles Definition of φ (AB-CD) dihedral angle A A B C D +! D B C φ (AB-CD) is + if clockwise - if counterclockwise #! " 360 if! >180! = $ %! if! < "180

4 Polypeptide structure can be described by backbone dihedral angles Variable backbone dihedrals '! i C i"1 " N i " C i # "C i '! i N i " C i # " C i ' " N i +1 Peptide plane dihedral! i,i +1 C i " # C i ' " # N i +1 # C i +1 ω tends to be planar due to delocalization of the C π electron and the nitrogen lone pair.! =180 0 ±10 0

5 Secondary structures are local backbone structures with repeating φ and ψ Common examples: α helix β strands The Ramachandran plot, or ψ vs. φ plot, is the best way to view secondary structures in terms of the backbone dihedral angles.

6 Regular α helix right-handed! = "60 0, # = "40 0

7 α helix! = "60 0, # = "40 0 right handed, clockwise looking down from the N-terminus H-bond between O of residue i and HN of residue i+4 N 3.6 residues 5.4 A H-bond C Pauling et al., PNAS, 1951

8 Why are α helices right-handed in nature? right handed left handed HB of Arg7 O of Arg7 O of Arg7 HB of Arg7 less steric collision more steric collision

9 Some residues have the left-handed helical φ and ψ left-handed! = +60 0, " = +40 0

10 Glycines frequently have positive φ angles Take home question Why do glycines often have the left-handed dihedrals! = +60, " = +40?

Helix electric dipole moment -0.42 ~ 3.5 Debye +0.42-0.20 +0.20 1 Debye =10!18 esu cm e! 1 angs = 4.8!10 "18 esu cm Wada, Adv.

11 Helix electric dipole moment ~ 3.5 Debye Debye =10!18 esu cm e! 1 angs = 4.8!10 "18 esu cm Wada, Adv. in Biophysics, 9, 1-63 (1976) Helix dipole can coordinate phosphate or sulphate binding

12 Example: the sulphate-binding protein (PDB code: 1SBP) SO 4 -

Examples of stabilization of helix by helix-helix packing H-bond energy ~

13 A single helix in solution is not stable. It must be stabilized by packing with other structural elements. Examples of stabilization of helix by helix-helix packing H-bond energy ~ 7 kj/mol, similar to the thermal energy in water. Thus H-bonds are not enough to keep a single helix stably locked.

14 Representation of helix by the helix wheel

15 Other unusual helical structures right-handed 3 10 helix! = "49 0, # = "26 0

16 3 10 helix 3 residues per turn H-bond (i,i+3)!," = #49,#26 α helix 3.6 residues per turn H-bond (i,i+4)!," = #60,#40 π helix 4.1 residues per turn H-bond (i,i+5)!," = #55,#70

Beginning and end of an α helix N-cap: The first residue of an α helix has non-helical Φ,Ψ dihedral angles, but participates, through its main-chain C=O group, in intra-helical hydrogen bonds.

17 Beginning and end of an α helix N-cap: The first residue of an α helix has non-helical Φ,Ψ dihedral angles, but participates, through its main-chain C=O group, in intra-helical hydrogen bonds. The side chain of the N-cap residue frequently accepts a hydrogen bond from the mainchain NH of the N3 residue. C-cap: The last residue of an α-helix has non-helical Φ,Ψ dihedral angles, but participates, through its main-chain N-H group, in intra-helical hydrogen bonds. The C-cap residue is often in the left-handed 3 10 helix conformation. Take home question What are the more likely amino acids for the N-cap? How about the C-cap?

18 ! = "135 0, # = β strands

19 β strands are NOT fully extended polypeptide chains Fully extended peptide! = "180 0, # = Anti-parallel β strands are slightly more stable than parallel β strands. 6 Å! = "140 0, # = 135 0! = "120 0, # = 115 0

20 Example: thioredoxin from E. coli

21 A single sheet in solution is also not stable. It must be stabilized by packing with helices or other sheets. dihydrofolate reductase V domain of Ig light chain retinol-binding protein

22 Non-repetitive structure: turns type I, most common type II, 2nd most common α helix 3 10 helix poly-pro Gly, left-handed 3 10 helix H-bond H-bond

23 Turns in antiparallel β strands type I type II

24 Ca trace of ubiquitin Protein sidechain conformation

25 not staggered staggered Example: valine χ 1 trans 180 +gauche 60 -gauche -60

26 Definition of sidechain χ 1 rotamer Regular, Ser Val, Ile, Thr -60 Hα -60 Hα CA-CB bond Hβ 2 C Hβ 1 Cγ / Oγ N Hβ C Cγ2 Cγ1/ Oγ1 N +60 Hα +60 Hα Hβ 1 Hβ 2 Cγ2 Hβ C N C N Cγ / Oγ Cγ1/ Oγ1 180 Hα 180 Hα Cγ / Oγ Hβ 1 Cγ1/ Oγ1 Cγ2 C N C N Hβ 2 Hβ

27 Sidechain conformation is dependent on backbone secondary structures due mainly to steric hindrance. Example of steric hindrance in determining the conformation of pentane (Dunbrack & Karplus, Nat. Struct. Biol., 1994).! 1 = 180,! 2 = 180, 0.00 kj/mol! 1 = 68,! 2 = 177, 3.6 kj/mol! 1 = 65,! 2 = 65, 7.5 kj/mol! 1 = 78,! 2 = 84, 14.9 kj/mol

28 Different values of φ and ψ yield different amount of steric hindrance at a given χ 1. Dunbrack & Karplus, Nat. Struct. Biol., 1994

29 (φ,ψ) dependent χ 1 preference for Valine Valine χ 1 = 180 Valine χ 1 = -60

30 (φ,ψ) dependent χ 1 preference for Isoleucine Isoleucine χ 1 = 180 Isoleucine χ 1 = -60

31 Effect of special residues on the backbone structure Gly often terminates an α helix, ~1/3 of all helices finish with Gly N- and C-terminal ends of the helix Gly C-cap

32 Proline also causes distortion or termination of helices N- and C-terminal ends of the helix Note: the closed ring constraints φ to be near -60

33 Proline causes a kink in α helix Proline in tight turns preceded by trans peptides No H-bond

34 cis - trans isomerization of proline X-X peptide 99.9% trans 0.1% cis X-Pro peptide ~70% trans ~30% cis

35 cis - trans isomerization of Proline in a turn

36 Polyproline helices type I!," = #75, residues per turn, right-handed, cis type II!," = #75, residues per turn, left-handed, trans collagen (GPP) n

Overview. The peptide bond. Page 1

Overview. The peptide bond. Page 1 Overview Secondary structure: the conformation of the peptide backbone The peptide bond, steric implications Steric hindrance and sterically allowed conformations. Ramachandran diagrams Side chain conformations