Programme Good morning and summary of last week Levels of Protein Structure - I Levels of Protein Structure - II

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1 Programme Good morning and summary of last week Levels of Protein Structure - I Levels of Protein Structure - II Break Exercise: Building a protein model by hand Summary of exercise Quiz! 1

2 Feedback Persons 2

3 Summary of Last Week Walk-through of course plan See presentation and website: Course

4 Group Work MOTIVATION: General qualification to be able to work with (almost) anybody. CHALLENGE: Some students have not yet shown up and need to join other groups or form new. Incompatibilities within groups. SOLUTION: New groups can be formed when projects are initiated. Define new set of group rules. 4

5 Programme Good morning and summary of last week Levels of Protein Structure - I Levels of Protein Structure - II Break Exercise: Building a protein model by hand Summary of exercise Quiz! 5

6 Levels of Protein Structure Primary to Quaternary Structure 6

7 Learning Objectives After today you should be able to: Define the structural levels of proteins. Identify the structural units of the protein backbone. Create a model of a protein fragment given its backbone torsion angles. Explain why some backbone conformations are forbidden, i.e. not found in natural proteins. Name properties on which the amino acids can be grouped. Name more amino acids than you could before Tool Amino acid quiz! 7

8 Amino Acids Proteins are built from amino acids Amino group and acid group C ε S δ C γ Side chain at Cα C β Chiral, only one enantiomer found in proteins (L-amino acids) N C α C 20 natural amino acids O Methionine 8

9 How to Group Them? Many features Charge +/- Acidic vs. basic (pk a ) Polarity (polar/non-polar) Type, distribution Size Length, weight, volume, surface area Type (Aromatic/aliphatic) 9

10 The Amino Acids Val (V) Thr (T) Phe (F) Ala (A) His (H) Ser (S) Arg (R) Leu (L) Cys (C) Met (M) Asp (D) Ile (I) Asn (N) Trp (W) Lys (K) Glu (E) Gln (Q) Tyr (Y) Pro (P) 10 Gly (G)

11 Amino Acids A Ala C Cys D Asp E Glu F Phe G Gly H His I Ile K Lys L Leu M Met N Asn P Pro Q Gln R Arg S Ser T Thr V Val W Trp Y - Tyr Livingstone & Barton, CABIOS, 9, ,

12 The Evolution Way Based on Blosum62 matrix Measure of evolutionary substitution probability P 12

13 The Simple Aliphatic Val (V) Ala (A) Leu (L) Ile (I) 13 Met (M)

14 The Small Polar Ser (S) Cys (C) Thr (T) 14 Cystin

15 The Unusual P, G Also aliphatic Structural impact Gly (G) Strictly speaking, proline is an imino acid Pro (P) 15

16 The Acidic and Their Derivatives Asp (D) Asn (N) Glu (E) Gln (Q) 16

17 The Basic Arg (R) Lys (K) His (H) 17

18 The Aromatic Phe (F) His (H) Trp (W) Tyr (Y) 18

19 Programme Good morning and summary of last week Levels of Protein Structure - I Levels of Protein Structure - II Break Exercise: Building a protein model by hand Summary of exercise Quiz! 19

20 Proteins Are Polypeptides The peptide bond A polypeptide chain 20

21 Torsion Angles 21

22 Ramachandran Plot Allowed backbone torsion angles in proteins N H 22

23 Small Exercise (5 minutes) For the polypeptide on the left discuss the following with your neighbour: Why is the lower right quadrant a forbidden region in the Ramachandran plot? What makes Gly a special amino acid when it comes to Ramachandran plots? What about Pro? 23

Structure Levels Primary structure = Sequence (of amino acids) Secondary Structure = Helix, sheets/strands, bends, loops & turns (all defined by H-bond pattern in backbone) Structural Motif = Small,

24 Structure Levels Primary structure = Sequence (of amino acids) Secondary Structure = Helix, sheets/strands, bends, loops & turns (all defined by H-bond pattern in backbone) Structural Motif = Small, recurrent arrangement of secondary structure, e.g. Helix-loop-helix Beta hairpins EF hand (calcium binding motif) Many others Tertiary structure = Arrangement of Secondary structure elements within one protein chain MSSVLLGHIKKLEMGHS 24

Intramolecular vs. intermolecular contacts.

25 Quaternary Structure Assembly of monomers/subunits into protein complex Backbone-backbone, backbone-side-chain & side-chain-side-chain interactions: Intramolecular vs. intermolecular contacts. For ligand binding side chains may or may not contribute. For the latter, mutations have little effect. Myoglobin α Haemoglobin α β β α 25

26 Hydrophobic Core Hydrophobic side chains go into the core of the molecule but the main chain is highly polar. The polar groups (C=O and NH) are neutralized through formation of H-bonds. Myoglobin Surface 26 Interior

27 Hydrophobic vs. Hydrophilic Globular protein (in solution) Membrane protein (in membrane) Myoglobin Aquaporin 27

28 Hydrophobic vs. Hydrophilic Globular protein (in solution) Membrane protein (in membrane) Cross-section Myoglobin Cross-section Aquaporin 28

29 Characteristics of Helices Aligned peptide units Dipolar moment Ion/ligand binding Secondary and quaternary structure packing Capping residues The α helix (i i+4) Other helix types! (3 10, π) C N 29

30 Helix Types 30

31 Residue Patterns Helices Helix capping Amphiphilic residue patterns C N Sheets Amphiphilic residue patterns Residue preferences at edges vs. middle Special residues Proline Helix breaker Glycine In turns/loops/bends 31

32 β-sheets Multiple strands sheet Parallel vs. antiparallel Twist Thioredoxin Flexibility Vs. helices Folding Structure propagation (amyloids) Other 32

33 β-sheets Multiple strands sheet Parallel vs. antiparallel Twist Flexibility Vs. helices Folding Structure propagation (amyloids) Other 33

34 β-sheets Multiple strands sheet Parallel vs. antiparallel Twist Flexibility Vs. helices Folding Structure propagation (amyloids) Other 34

35 β-sheets Multiple strands sheet Parallel vs. antiparallel Twist Flexibility Vs. helices Folding Structure propagation (amyloids) Other 35

36 β-sheets Multiple strands sheet Parallel vs. antiparallel Twist Antiparallel Parallel Strand interactions are non-local Flexibility Vs. helices Folding 36

37 Turns, Loops & Bends Between helices and sheets On protein surface Intrinsically unstructured proteins 37

38 Summary The backbone of polypeptides form regular secondary structures. Helices, sheets, turns, bends & loops. These are the result of local as well as nonlocal interactions. Secondary structure elements are associated with specific residue patterns. 38

39 α-sheets and β-helices α-sheet β-helix Theoretical Real 1M8N 39

40 Break! Be

41 Programme Good morning and summary of last week Levels of Protein Structure - I Levels of Protein Structure - II Break Exercise: Building a protein model by hand Summary of exercise Quiz! 41

42 Assistant Ole Lund 42

43 M1 Protein Influenza protein. Covers the ribonucleoprotein capsid below the membrane. Helix bundle. 43

44 M1 for Exercise One helix per group Split in two parts, build then switch and check. Assist each other in connecting the helices when done! 44

45 Building Blocks C α Peptide unit (amide) O C N COOH OH Indole C/CH/CH 2 /CH 3 S/SH N O C Amide Phenyl Imidazole Guanidine H-bond NH 2 /NH

46 Building Blocks Cε Sδ On-1 Cn-1 N Cα χ3 Nn+1 C O Residue N Cα C O Cγ χ2 C β χ 1 O Single amino acid N φ Cα ψ C O O Methionine 46

47 Procedure 1. Build backbone in extended conformation (strand). 2. Twist to align all peptide units (look at the C=O groups). 3. Add H-bonds (i+4) to construct an ideal α-helix. 4. Add side chains along the way (pointing down ). 5. Adjust side chain torsion angles. C N 47

48 Programme Good morning and summary of last week Levels of Protein Structure - I Levels of Protein Structure - II Break Exercise: Building a protein model by hand Summary of exercise Quiz! 48

49 Programme Good morning and summary of last week Levels of Protein Structure - I Levels of Protein Structure - II Break Exercise: Building a protein model by hand Summary of exercise Quiz! 49

Fundamentals of Protein Structure

Outline Fundamentals of Protein Structure Yu (Julie) Chen and Thomas Funkhouser Princeton University CS597A, Fall 2005 Protein structure Primary Secondary Tertiary Quaternary Forces and factors Levels