Amino Acids and Peptides: Structure, Properties, and Reactions

5.1 Amino Acids

The Structure of an α-Amino Acid

Amino acids are the building blocks of proteins, each containing a central α-carbon atom bonded to four distinct groups. Their structure and properties are fundamental to understanding protein chemistry.

• α-Carbon: The central carbon atom in an amino acid, to which the following groups are attached:

  • Amino group (-NH2)

  • Carboxylic acid group (-COOH)

  • Side chain (R group): Unique to each amino acid and determines its properties

  • Hydrogen atom

• Chirality: When the α-carbon is attached to four different groups, it is a chiral (asymmetric) center. All standard amino acids except glycine are chiral.

• Zwitterion: At neutral pH, the amino group is protonated (-NH3+) and the carboxyl group is deprotonated (-COO-), resulting in a molecule with both positive and negative charges.

Example: Glycine is the only non-chiral amino acid because its R group is a hydrogen atom.

α-Amino Acid Stereochemistry

The spatial arrangement of atoms around the α-carbon leads to stereoisomerism in amino acids, which is crucial for protein structure and function.

• Chirality: Most amino acids exist as two enantiomers (L and D forms), which are non-superimposable mirror images.

• L- and D-forms: Proteins are composed almost exclusively of L-amino acids.

• Fischer Projection: A two-dimensional representation used to depict stereochemistry.

Example: L-alanine and D-alanine are enantiomers; L-alanine is the form found in proteins.

Classification of Naturally Occurring Amino Acids

The 20 standard amino acids are classified based on the properties of their side chains (R groups), which influence protein structure and function.

• Nonpolar Aliphatic: Glycine, Alanine, Valine, Leucine, Isoleucine, Proline, Methionine

• Aromatic: Phenylalanine, Tyrosine, Tryptophan

• Polar Uncharged: Serine, Threonine, Cysteine, Asparagine, Glutamine

• Positively Charged (Basic): Lysine, Arginine, Histidine

• Negatively Charged (Acidic): Aspartic acid, Glutamic acid

Example: Tyrosine is an aromatic amino acid with a polar side chain.

General Properties of Amino Acids

Amino acids exhibit characteristic chemical properties, including UV absorption, ionization, and the ability to undergo posttranslational modifications.

• UV Absorption: Aromatic amino acids (tyrosine and tryptophan) absorb UV light strongly at 280 nm, which is used to quantify protein concentration. Nucleic acids absorb most strongly at 260 nm.

• Ionization and pKa Values: Amino acids contain ionizable groups with characteristic pKa values:

Group Type	Typical pKa Range
α-Carboxyl	3.5–4.0
Side-chain carboxyl (Asp, Glu)	4.0–4.8
Imidazole (His)	6.5–7.4
Cysteine (–SH)	8.0–9.0
Phenolic (Tyr)	9.5–10.5
α-Amino	8.0–9.0
Side-chain amino (Lys)	9.8–10.4
Guanidinium (Arg)	>12

• Titration Curves: The charge on an amino acid (e.g., histidine) varies with pH. The isoelectric point (pI) is the pH at which the net charge is zero.

• Posttranslational Modifications: Amino acids can be chemically modified after translation, affecting signaling, structure, and gene expression.

Examples of Modifications: Phosphoserine, 4-hydroxyproline, N-acetyllysine, γ-carboxyglutamate.

5.2 Peptides and the Peptide Bond

Peptide Bond Formation between Amino Acids

Peptide bonds link amino acids together to form peptides and proteins. This process is central to protein biosynthesis.

• Condensation Reaction: The peptide bond forms via a condensation reaction between the α-carboxyl group of one amino acid and the α-amino group of another, releasing water.

• Energetics: Peptide bond formation is not thermodynamically favorable and is coupled to ATP hydrolysis during protein synthesis.

Equation:

$\text{Amino acid}_1 + \text{Amino acid}_2 \rightarrow \text{Dipeptide} + H_2O$

Structure of the Peptide Bond

The peptide bond has unique structural properties due to electron delocalization.

• Planarity: The peptide bond is planar and rigid due to resonance between the carbonyl and amide nitrogen, restricting rotation.

• Stability: This planarity contributes to the stability of protein secondary structures.

Peptide Bond Cleavage

Peptide bonds can be hydrolyzed, but they are generally stable under physiological conditions.

• Hydrolysis: The standard free energy change ($\Delta G^\circ$) for peptide bond hydrolysis is about –10 kJ/mol.

• Stability: Peptides are stable unless exposed to strong acid at high temperature or a catalyst (protease).

• Proteases: Enzymes that catalyze the cleavage of specific peptide bonds.

Sequence Specificities for Proteases

Different proteases cleave peptide bonds at specific amino acid sequences.

Enzyme	Preferred Site	Source
Trypsin	R, K (Arg, Lys)	Digestive systems of animals
Chymotrypsin	F, Y, W, L, M (Phe, Tyr, Trp, Leu, Met)	Digestive systems of animals
Thrombin	R (Arg)	Blood (clotting)
V8 protease	E (Glu)	Staphylococcus aureus
Cyanogen bromide	M (Met)	Chemical reagent
Carboxypeptidase A	C-terminal (except R, K, P)	Pancreas
Carboxypeptidase B	C-terminal R, K	Pancreas

Additional info: Table entries inferred and summarized for clarity.

Oligopeptides and Polypeptides

Peptides are classified by the number of amino acid residues they contain.

• Oligopeptides: Chains of 3–15 amino acids.

• Polypeptides: Chains containing more than 15 amino acids.

Important Peptide Regions

Peptides have distinct regions that determine their chemical and biological properties.

• Amino (N-) terminus: The end with a free amino group.

• Carboxy (C-) terminus: The end with a free carboxyl group.

• Main chain (backbone): The repeating sequence of atoms that forms the core of the peptide.

• Side chains: The variable R groups that project from the main chain.

Common Modifications of Amino- and Carboxy-Termini in Peptides

The N- and C-termini of peptides can be chemically modified, affecting peptide stability and function.

• N-formyl group

• N-acetyl group

• C-terminal amide

Peptides and Proteins as Polyampholytes

Peptides and proteins contain multiple ionizable groups, allowing them to act as polyampholytes (molecules with both acidic and basic groups).

• Ionization Behavior: As pH increases, the overall charge on a peptide becomes more negative; as pH decreases, it becomes more positive.

• Isoelectric Point (pI): The pH at which the net charge is zero.

Example: The titration curve of a tetrapeptide shows stepwise ionization of its groups as pH changes.