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 foldingTowards 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 sub-optimal

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 structureMaximize good interactionMinimize bad interactions

• helix

• sheets

• turns

• others

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 -helix formation

• Proline: too constrained– Prolines tend to disrupt stretches of a-helix

• Glycine: too flexible

Type of amino acid influences -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

strands

sheet

• More extended structure than helix

• H-bond pairs not necessarily anywhere near each other in sequence

• strands can link to form sheets or barrels

turns

• Connect the ends of antiparallel strands

• Can be extended: less constraint

• Can be compact: lots of constraint– Prolines and glycines are particularly good for

tight turns