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Protein “folding” occurs due to the intrinsic
chemical/physical properties of the 1° structure
“Unstructured”
“Disordered”
“Denatured”
“Unfolded”
“Structured”
“Native conformation”
“Folded”
Driving force for protein folding
• Entropy
– Amino acids lose entropy (degrees of freedom)
upon folding
– Water molecules gain more entropy when the
protein folds
Driving force for protein folding
Towards lowest free energy (G)
Proteins are not static “rocks”
• Form multiple stable conformations
• Often conformation change is
important for function
• Protein “breathing”/inherent flexibility
HIV-1 protease
Contribution of water to protein folding
• Unfolded protein
– Water is highly structured (entropy)
• Form the optimal number of hydrogen bonds
(enthalpy)
• Hydrophobic side chains
• Hydrophilic side chains/groups (slightly suboptimal H-bonding)
Contribution of water to protein folding
•
Folded protein
– Polypeptide is ordered (entropy)
– Max hydrogen bonds are formed (enthalpy)
•
2° structure
1. Hydrophobic residues are buried within the
protein
2. Hydrogen bonding (and salt
bridges/attractive ionic forces) are
maximized
Peptide bond constrains protein structure
Resonance: partial double bond character
The peptide bond is flat/planar
Elements of 2 structure
Maximize good interaction
Minimize bad interactions
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a helix
b sheets
b turns
others
a helix
H-bond: Carboxyl oxygen’s residue and amino
hydrogen’s residue are separated by three a.a.s
Side chains decorate the outside of
the helix
Side chains are involved in alpha-helix
formation
Stabilize (or destabilize)
Type of amino acid influences a-helix
formation
• Proline: too constrained
– Prolines tend to disrupt stretches of a-helix
• Glycine: too flexible
Type of amino acid influences a-helix
formation
• Adjacent side chains can electrostatically
interact (stabilizing/destabilizing)
• Adjacent side chains can sterically interact
(destabilizing)
• Side chains 3 or 4 residues apart can be
attractive (stabilizing) or repulsive (destabilizing)
• Proline and glycine residues (destabilizing)
• Terminal side chains prefer compatibility with the
helix’s polarity
b strands
b sheet
• More extended structure than helix
• H-bond pairs not necessarily anywhere
near each other in sequence
• b strands can link to form b sheets or b
barrels
b turns
• Connect the ends of antiparallel b strands
• Can be extended: less constraint
• Can be compact: lots of constraint
– Prolines and glycines are particularly good for
tight turns