1. Protein “folding” occurs due to the intrinsic chemical/physical properties of the 1° structure “Unstructured” “Disordered” “Denatured” “Unfolded” “Structured” “Native conformation” “Folded”

2. Driving force for protein folding Entropy –Amino acids lose entropy (degrees of freedom) upon folding –Water molecules gain more entropy when the protein folds

3. Driving force for protein folding Towards lowest free energy (G)

4. Proteins are not static “rocks” Form multiple stable conformations Often conformation change is important for function Protein “breathing”/inherent flexibility HIV-1 protease

5. 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)

6. 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

7. Peptide bond constrains protein structure Resonance: partial double bond character The peptide bond is flat/planar

8. Elements of 2 structure Maximize good interaction Minimize bad interactions  helix  sheets  turns others

9.  helix

10. H-bond: Carboxyl oxygen’s residue and amino hydrogen’s residue are separated by three a.a.s

12. Side chains decorate the outside of the helix

13. Side chains are involved in alpha-helix formation Stabilize (or destabilize)

14. Type of amino acid influences  -helix formation Proline: too constrained –Prolines tend to disrupt stretches of a-helix Glycine: too flexible

15. 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

17.  strands

18.  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

22.  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