Amino Acids and Peptides: Structure, Properties, and Biochemical Roles

5.1 Amino Acids

The Structure of an α-Amino Acid

α-Amino acids are the building blocks of proteins, each containing a central α-carbon atom bonded to an amino group, a carboxylic acid group, a hydrogen atom, and a unique side chain (R group). The structure and properties of amino acids are fundamental to understanding protein chemistry.

• α-Carbon: The central carbon atom to which four different groups are attached.

• Functional Groups: Includes an amino group (-NH2), a carboxylic acid group (-COOH), a hydrogen atom, and a side chain (R group) specific to each amino acid.

• Chirality: When the α-carbon is attached to four different groups, it is chiral (asymmetric), except in glycine where the R group is hydrogen.

• Zwitterion Formation: At neutral pH, the amino group is protonated and the carboxylic acid group is deprotonated, resulting in a molecule with both positive and negative charges (zwitterion).

• Example: Alanine has a methyl group as its R group.

α-Amino Acid Stereochemistry

The stereochemistry of amino acids is crucial for protein structure and function. Most amino acids are chiral and exist as stereoisomers.

• Chirality: All common amino acids except glycine have a chiral α-carbon.

• Enantiomers: L-alanine and D-alanine are mirror images (enantiomers).

• Fischer Projection: A 2D representation used to distinguish stereoisomers.

• Biological Relevance: Proteins are composed almost exclusively of L-amino acids.

Classification of Naturally Occurring Amino Acids

The 20 common amino acids found in proteins are classified based on the properties of their side chains.

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

• Nonpolar Aromatic: Phenylalanine, Tyrosine, Tryptophan

• Polar Uncharged: Serine, Threonine, Asparagine, Glutamine

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

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

• Example: Tyrosine is aromatic and polar due to its hydroxyl group.

General Properties of Amino Acids

Amino acids exhibit unique chemical properties, including UV absorption and ionization behavior, which are important for protein analysis and function.

• UV Absorption: Aromatic amino acids (tyrosine and tryptophan) absorb UV light at 280 nm, allowing protein quantification.

• Nucleic Acids: Absorb most strongly at 260 nm.

• Ionizable Groups: Amino acids have groups with characteristic pKa values, affecting their charge at different pH levels.

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 Curve of Histidine

The titration curve of histidine illustrates how its charge changes with pH due to ionizable groups.

• Charge Variation: Histidine's charge ranges from +2 to –1 as pH increases.

• pKa Values: Indicate the pH at which each ionizable group loses a proton.

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

• Equation: $\text{pI} = \frac{pK_{a1} + pK_{a2}}{2}$ (for amino acids with two ionizable groups)

Posttranslational Modification of Amino Acids

Posttranslational modifications alter amino acids after protein synthesis, affecting protein function and regulation.

• Functions: Signaling pathways, calcium binding, stabilizing structures (e.g., collagen), gene expression/suppression.

• Examples: 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 to form peptides and proteins through a condensation reaction that releases water.

• Condensation Reaction: Two amino acids join, forming a peptide bond and releasing H2O.

• Energetics: The reaction is not thermodynamically favorable and is coupled to ATP hydrolysis during protein biosynthesis.

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

Structure of the Peptide Bond

The peptide bond is characterized by electron delocalization, resulting in a planar and stable structure.

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

• Stability: Delocalization of electrons prevents free rotation around the bond.

Peptide Bond Cleavage

Peptide bonds can be hydrolyzed by strong acid, high temperature, or specific enzymes called proteases.

• Hydrolysis: $\Delta G^\circ$ for peptide bond hydrolysis is about –10 kJ/mol.

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

• Proteases: Enzymes that cleave specific peptide bonds.

Sequence Specificities for Proteases

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 cascade
V-8 protease	E (Glu)	Staphylococcus aureus
Cyanogen bromide	M (Met)	Chemical reagent
Additional info:	Other proteases have unique specificities	Various sources

Oligopeptides

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

• Oligopeptides: Chains of 3–15 amino acid residues.

• Polypeptides: Chains containing more than 15 residues.

• Example: A tetrapeptide contains four amino acids.

Important Peptide Regions

Peptides and proteins have distinct regions, including the amino (N-) terminus, carboxy (C-) terminus, main chain, and side chains.

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

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

• Main Chain: The repeating backbone of the peptide.

• Side Chains: The variable R groups projecting from the main chain.

Common Modifications of Amino- and Carboxy-Termini in Peptides

Peptide termini can be chemically modified, affecting protein stability and function.

• N-formyl group: Blocks the N-terminus.

• N-acetyl group: Blocks the N-terminus.

• C-terminal amide: Blocks the C-terminus.

• Example: N-acetylation is common in eukaryotic proteins.

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 becomes more negative; as pH decreases, it becomes more positive.

• Buffering Capacity: Proteins can buffer changes in pH due to their ionizable groups.

• Example: The titration curve of a tetrapeptide shows stepwise changes in charge as pH changes.