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Non-covalent forces that stabilise the folded protein structure:
1
...
Electrostatic interactions
3
...
Hydrophobic effect
Type
example
Enthalpy H (kcal
Entropy T S (kcal
-1
mol )
mol-1) G=- T S
Van der waals

-0
...
4
interaction


• Any spontaneous change needs to have an increase in entropy
• The unfolded state = higher entropy than folded state

What is the basis for the hydrophobic effect, i
...
The tendency for hydrophobic amino-acids
to cluster together?
• Water molecules in contact with a hydrophobic side-chain cannot form any type of
non-covalent bond with that side-chain, and so they form tighter bonds with each
other (water to water H bonds)
• This ice like structure that surrounds each hydrophobic amino-acid side-chain can be
released, and the water molecules allowed grater freedom, if the hydrophobic sidechains all cluster together in the core of the protein
• The driving force for protein folding is the need for water molecules to increase its
entropy
• Greater freedom means greater entropy, and thus the hydrophobic effect is driven
by the tendency for water molecules to gain greater freedom --> greater entropy

Do H bonds each contribute 3kcal/mol to the free energy of folding?
• No – only about 1 kcal/mol as they can also form (weak) H bonds with water
molecules in the unfolded state

•

So they only have 1 kcal/mol due to the equilibrium between the folded and
unfolded States


Do electrostatic interactions each contribute 5kcal/mol to the free energy of folding?
• No-because the charges are fully solvated (neutralised) by water in the unfolded
state
• The entropic contribution of 1kcal/mol remains

Entropy of folding
• Entropy can be related to the number of states or degrees of freedom of the system
• S = k ln W --> Boltzmann's equation
• k = Boltzmann’s constant
• W = number of states = for a molecule W is the number of different conformations
For one molecule:
• S=NA k ln W (NA = Avogadro’s number)
• Therefore S = R ln W (R = gas constant = 2 cal K-1 mol-1; R = NAk)
For a mole of protein:
• S = Snative – Sunfolded
= R ln Wn – R ln Wu
= R ln (Wn / Wu)
• Wn = 1 as there is only 1 native conformation
• Wu = 10100 if there are 100 residues and if for every residue there are 10
conformations
• Therefore Sfolding = R ln (1/10100)
= -0
...
e
...
024 kcal/mol/ 2 of buried surface area


• The principle driving force for protein folding (or protein-protein interactions) in
aqueous solution is the increased entropy of the water molecules that results from
burying hydrophobic amino-acid side-chains



Protein folding – experimental observations
1
...
Is a fast process (amino acid sequence is formed by a ribosome which adds an amino
acid each second and takes just 1 second for a protein to fold)
3
...
Thermodynamic measurements suggest G= 10kcal/mol
5
...
g
...
g
...
g

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