Stereochemistry of a-Amino Acids

Stereochemistry of the α-Amino Acids

• α-Amino acids' stereochemistry is designated as D- or L-, which is best visualized from its Fischer projection.
• There is a preference for L-amino acids in proteins.
• The preference for L-amino acids in natural proteins has two important consequences:
  • The surface of any given protein is asymmetric, which is the basis for the highly specific molecular recognition of binding targets by proteins.
  • The stereochemistry of the amino acids plays an important role in the formation of so-called "secondary structure" and thereby the overall structure of proteins.

Properties of the Amino Acid Side Chains

• The 20 common amino acids are classified by their side chains:
  • Aliphatic
  • Hydroxyl or sulfur-containing
  • Aromatic
  • Basic
  • Acidic and their amides
• The more hydrophobic amino acids, such as isoleucine, are usually found within the core of a protein molecule, where they are shielded from water.
• Proline is the only amino acid in which the side chain forms a covalent bond with the α–amino group.

Peptides and the Peptide Bond

• While hydrolysis of peptide bonds is thermodynamically favored in aqueous solutions, the reaction is exceedingly slow at physiological pH and temperature.
• Peptide bond hydrolysis can be achieved by:
  • Strong mineral acid (e.g., 6 M HCl) cleaves all peptide bonds (including the Asn and Gln amide bonds).
  • Chemicals that cleave at specific sites (e.g., CNBr cleaves at Met).
  • Proteolytic enzymes (proteases) that cleave at specific sites.

Proteins: Polypeptides of Defined Sequence

• Every protein has a defined number and order of amino acid residues, referred to as the primary structure of the protein.
• The primary structure of a protein corresponds to the DNA (gene) sequence.
• The genetic code is responsible for the translation of DNA into protein.

Post-translational Modification

• Many proteins, such as insulin, undergo post-translational modification.

Secondary Structure: Regular Ways to Fold the Polypeptide Chain

• There are two main types of secondary structures:
  • The α-helix, where the hydrogen bonds are within a single polypeptide chain and are almost parallel to the helix axis.
  • The β-sheet, where the hydrogen bonds are between adjacent chains and are nearly perpendicular to the chains.
• The 3₁₀ helix is less common than the α-helix.
• Secondary structures can be amphiphilic (or amphipathic), displaying a predominantly hydrophobic face opposite a predominantly hydrophilic face.
• The α-helix has side chains of similar polarity every 3–4 residues.
• The β-strand has alternating polar and nonpolar side chains.

Fibrous Proteins: Structural Materials of Cells

• Collagen is a fibrous protein that forms the matrix material in bone, constitutes the major portion of tendons, and is an important constituent of skin.
• The basic unit of the collagen fiber is the tropocollagen molecule, a triple helix of three polypeptide chains.
• The chains wrap around each other in a right-handed sense, with hydrogen bonds between the chains.
• Every third residue can be only glycine.
• Hydroxyproline and hydroxylysine are present in collagen.
• A repetitive motif in the sequence is of the form Gly–X–Y, where X is often proline and Y is proline or hydroxyproline.

Scurvy and Collagen Weakening

• Scurvy is a connective tissue disease caused by a deficiency in Vitamin C (ascorbic acid), leading to weakened collagen fibers.
• The disease is caused by failure to hydroxylate prolines and lysines in collagen, resulting in less hydrogen bonding between the chains of tropocollagen.

Cross-Linking in Collagen

• Lysine side chains can oxidize to aldehyde derivatives, which can react with either a lysine residue or with one another to produce a cross-link.
• This process continues through life, making the collagen steadily less elastic and more brittle.

Factors Determining Secondary and Tertiary Structure

• The stability of the folded structure of a globular protein depends on the interplay of three factors:
  • The unfavorable conformational entropy change, which favors the unfolded state.
  • The favorable enthalpy contribution arising from intramolecular interactions.
  • The favorable entropy change arising from the burying of hydrophobic groups within the molecule.
• The role of disulfide bonds in stabilizing the folded structure.

Dynamics of Globular Protein Structure

• The folding of globular proteins from their denatured conformations is a remarkably rapid process, often complete in less than a second.
• Protein folding is not a completely random search through a vast conformational space, but rather takes place through a series of intermediate states.