protein structure elements primary to quaternary structure
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Protein Structure Elements
Primary to Quaternary Structure
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Learning Objectives
• After this lesson you should be able to:
– Define the structural levels of proteins.– Identify regular secondary structure elements.– Identify the structural units of the protein backbone.– Explain why some backbone conformations are favoured
and some are “forbidden” (not found in natural proteins).– Name properties on which the amino acids can be
grouped.– Explain the driving forces behind protein folding related
to the properties of the backbone and the side chains.
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Proteins Are Polypeptides• The peptide bond • A polypeptide chain
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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…
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• Myoglobin
• Haemoglobin
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.
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A Bit About Protein Folding
How and why proteins fold
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Why Fold?
• Hydrophobic collapse– Hydrophobic residues cluster to “escape”
interactions with water.– Polar backbone groups form secondary
structure to satisfy hydrogen bonding donors and acceptors.
– Initially formed structure is in molten globule state (ensemble).
– Molten globule condenses to native fold via transition state
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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
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Hydrophobic vs. Hydrophilic
• Globular protein (in solution)
• Membrane protein
Myoglobin Aquaporin
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Hydrophobic vs. Hydrophilic
• Globular protein (in solution)
• Membrane protein
Myoglobin Aquaporin
Cross-section Cross-section
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From Unfolded to Native State
G = H - T×S-------------------------G: Free (Gibbs)
energyH: Enthalpy
(interactions)S: Entropy
(conformations/states)
E
U
F
T
G
Unfolded state, ensemble
Native fold, one structure
Transition state, one or more narrow ensembles
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Protein Stability & Dynamics
• Folded proteins are:
– Only marginally stable (enthalpy and entropy almost balance at physiological temperatures)
• Allows for easy degradation and reuse.• Amyloid exception.
– Dynamic• “Breathing” motions on pico- to nanosecond scale.• Allows substrates/products to enter/leave enzymes.• Allows allosteric regulation of activity.
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Amino Acids• Proteins are built from
amino acids
• Amino group and acid group
• Side chain at C
• Chiral, only one enantiomer found in proteins (L-amino acids)
• 20 natural amino acids
N
O
CC
C
C
C
S
Methionine
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Amino Acid Properties
• Many features– Charge +/-
• Acidic vs. basic (pKa)
– Polarity (polar/non-polar)• Type, distribution
– Size• Length, weight, volume, surface area
– Type (Aromatic/aliphatic)
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Grouping Amino Acids
Livingstone & Barton, CABIOS, 9, 745-756, 1993
A – AlaC – CysD – AspE – GluF – PheG – GlyH – HisI – IleK – LysL – Leu
M – MetN – AsnP – ProQ – GlnR – ArgS – SerT – ThrV – ValW – TrpY - Tyr
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The Evolution Way
• Based on Blosum62 matrix
• Measure of evolutionary substitution probability
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Backbone Properties
• Amide bond planarity • 2 degrees of rotational freedom per residue
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Ramachandran Plot
• Allowed backbone torsion angles in proteins
N
H
Residue
Peptide bond
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Torsion Angles
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Characteristics of Helices
• Backbone interactions are local
• Aligned peptide units Dipolar moment
N
C
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Helix Types
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-Sheets
• Multiple strands sheet– Parallel vs. antiparallel– Twist
• Strand interactions are non-local
• Flexibility– Vs. helices– Folding
Antiparallel Parallel
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-Sheets
Thioredoxin
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-Sheets
Thioredoxin
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-Sheets
Thioredoxin
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-Sheets
Thioredoxin
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Not All -Sheets Are Flat
• Nitrophorin • Thioredoxin
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Residue Patterns
• Helices– Helix capping– Amphiphilic residue
patterns
• Sheets– Amphiphilic residue
patterns– Residue preferences at
edges vs. middle
• Special residues– Proline
• Helix breaker
– Glycine• In turns/loops/bends
N
C
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Turns, Loops & Bends Revisited
• Between helices and sheets
• On protein surface
• Intrinsically “unstructured” proteins
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Summary
• The backbone of polypeptides form regular secondary structures.– Helices, sheets, turns, bends & loops.
• These are the result of local as well as non-local interactions.
• Secondary structure elements are associated with specific residue patterns.
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-sheet and -helices
-sheet -helix
1M8NTheoretical Real