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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 • • • • 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