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Levels of Protein Structure Primary to Quaternary Structure 1 Learning Objectives After today you should be able to: – Define the structural levels of proteins. – Identify the structural units of the protein backbone. – 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 One and three letter codes 2 Amino Acids Proteins are built from amino acids Ce Amino group and acid group Sd Cg Side chain at Ca Cb Chiral, only one enantiomer found in proteins (L-amino acids) N Ca C O 20 natural amino acids Methionine 3 L-amino acids in Living organisms N: 14 C: 12 O: 16 4 How to Group Them? Many features – Charge +/• Acidic vs. basic (pKa) – Polarity (polar/non-polar) • Type, distribution – Size • Length, weight, volume, surface area – Type (Aromatic/aliphatic) 5 The Amino Acids Thr (T) Phe (F) Val (V) Ala (A) His (H) Arg (R) Ser (S) Leu (L) Cys (C) Asp (D) Met (M) Lys (K) Asn (N) Ile (I) Trp (W) Glu (E) Gln (Q) Tyr (Y) Pro (P) Gly (G) 6 Amino Acids A – Ala C – Cys D – Asp E – Glu F – Phe G – Gly H – His I – Ile K – Lys L – Leu Livingstone & Barton, CABIOS, 9, 745-756, 1993 7 M – Met N – Asn P – Pro Q – Gln R – Arg S – Ser T – Thr V – Val W – Trp Y - Tyr Blosum62 substitution matrix 8 The Evolution Way Based on Blosum62 matrix Measure of evolutionary substitution probability 9 The Simple Aliphatic Val (V) Ala (A) Leu (L) Met (M) Ile (I) 10 The Small Polar Ser (S) Cys (C) Thr (T) Cystin 11 The Unusual P, G Also aliphatic Structural impact Gly (G) Strictly speaking, proline is an imino acid Pro (P) 12 The Acidic and Their Derivatives Asp (D) Asn (N) Glu (E) Gln (Q) 13 The Basic Arg (R) Lys (K) 14 His (H) The Aromatic Phe (F) His (H) Trp (W) Tyr (Y) 15 Proteins Are Polypeptides The peptide bond A polypeptide chain 16 Ramachandran Plot Allowed backbone torsion angles in proteins N H 18 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? 19 Structure Levels Primary structure = Sequence (of amino acids) MSSVLLGHIKKLEMGHS… 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 20 Quaternary Structure Assembly of monomers/subunits into protein complex Myoglobin a – Backbone-backbone, backbone-side-chain & side-chain-side-chain interactions: Haemoglobin • Intramolecular vs. intermolecular contacts. • For ligand binding side chains may or may not contribute. For the latter, mutations have little effect. 21 a b b a 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 Interior 22 Hydrophobic vs. Hydrophilic Globular protein (in solution) Membrane protein (in membrane) Myoglobin Aquaporin 23 Hydrophobic vs. Hydrophilic Globular protein (in solution) Membrane protein (in membrane) Cross-section Cross-section Myoglobin Aquaporin 24 Characteristics of Helices Aligned peptide units Dipolar moment Ion/ligand binding Secondary and quaternary structure packing Capping residues The a helix (i→i+4) Other helix types! (310, p) C N 25 Helix Types 26 b-Sheets Multiple strands sheet Thioredoxin – Parallel vs. antiparallel – Twist – Coil regions between the secondary structure elements 28 b-Sheets Multiple strands sheet – Parallel vs. antiparallel – Twist 29 b-Sheets Multiple strands sheet – Parallel vs. antiparallel – Twist 30 b-Sheets Multiple strands sheet – Parallel vs. antiparallel – Twist 31 b-Sheets Multiple strands sheet Antiparallel – Parallel vs. antiparallel – Twist Strand interactions are non-local Flexibility – Vs. helices – Folding 32 Parallel Summary Amino acids in Living organisms have Lconfiguration One & three letter codes Groups of amino acids: hydrophobic ... The backbone of polypeptides form regular secondary structures. – Helices, sheets & loops. 33 Building Blocks Ca Peptide unit (amide) COOH O OH C N C/CH/CH2/CH3 O Indole N C Amide S/SH H-bond Phenyl Imidazole Guanidine NH2/NH3+ 34 Building Blocks Ce Sd On-1 Cn-1 N Ca Nn+1 C O Residue N Ca C O c3 Cg O c2 C b c 1 Single amino acid N f Ca y C O O Methionine 35 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 ahelix. 4. Add side chains along the way (pointing “down”). 36 C N