Peptides: Structure and Function

Amide Bond Formation

• Amino acids join via amide bonds (peptide bonds).
• A carboxylic acid reacts with an amine, requiring a coupling reagent because:
  • Carboxylic acid is not a great electrophile.
  • Combining an amine and carboxylic acid results in an acid-base reaction instead.
• Coupling reagents make the carboxylic acid more reactive.

Peptide Synthesis

• Unprotected amino acids can yield multiple dipeptide products.
• Peptides are written with the N-terminus on the left.
• Protecting groups are used to ensure only one target product is formed.

Peptide Bond Structure

• Amide nitrogen's lone pair is delocalized towards the carbonyl group oxygen.
• Peptide bonds are:
  • Relatively unreactive.
  • Rigid and planar, with restricted rotation of the O-C-N bonds.

Peptides

• Polymers of amino acids named by the number of monomers (di-, tri-, polypeptide).
• Written with the N-terminus on the left.
• Proteins are generally peptides with greater than 50 amino acids.

Peptide Properties

• Primary structure: sequence of amino acids.
• Side chain properties (ionization, hydrogen-bonding) influence peptide properties.
• Restricted rotation of O-C-N bonds.
• Sequential $α$-carbons are usually in a trans relationship.

Peptide, Protein Shape and Structure

• Primary structure: sequence of amino acids.
• Secondary structure: segments of structure along the chain (e.g., $α$-helix, turns, $β$-sheet).
• Tertiary structure: how secondary structural elements fit together.
• Quaternary structure: how proteins or independent peptide chains come together.
• Aqueous environment: polar side chains exposed, nonpolar side chains buried to maximize favorable non-covalent interactions.
• Hydrogen bonding between amide bonds stabilizes secondary structures.

Secondary Structure Example – Alpha Helix

• The $NH$ from an amide hydrogen bonds with the $CO$ of a different amide four amino acids along the chain.
• The consistent pattern of hydrogen bonds stabilizes the helical secondary structure.

Impact of Amino Acid Change

• Even a single amino acid change can alter protein shape.
• Sickle-cell anemia: glutamic acid replaced by valine in hemoglobin, causing protein aggregation.

Disulfide Bridges

• Can stabilize secondary or tertiary structures.
• Cysteine contains a thiol functional group that can oxidize to form a disulfide bond.
• Disulfide bridges can link remote ends of the peptide.

Disulfide Bridges – Insulin Example

• Insulin: two peptide chains connected/stabilized by three disulfide bonds (one intrachain, two interchain).