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

5.1 Amino Acids

The Structure of an α-Amino Acid

Amino acids are the building blocks of proteins and possess a central α-carbon atom to which four distinct groups are attached: an amino group, a carboxylic acid group, a hydrogen atom, and a variable side chain (R group). This structure imparts unique chemical properties to each amino acid.

• α-Carbon: The central carbon atom in amino acids; it is an asymmetric center when the R group is not hydrogen.

• Functional Groups: The amino group (–NH2), carboxylic acid group (–COOH), and side chain (R group) define the chemical nature of each amino acid.

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

• Example: Glycine is the simplest amino acid, with R = H.

α-Amino Acid Stereochemistry

The stereochemistry of amino acids is crucial for protein structure and function. Most amino acids are chiral, meaning they have non-superimposable mirror images.

• Chirality: When four different groups are attached to the α-carbon, it is chiral (a stereocenter).

• Fischer Projection: A 2D representation used to depict stereochemistry.

• L- and D- Isomers: L-alanine is the mirror image of D-alanine; these are called enantiomers.

• Exception: Glycine is achiral because its R group is hydrogen.

• Example: All amino acids in proteins are L-isomers.

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 and Tryptophan are aromatic amino acids with UV absorbance properties.

General Properties of Amino Acids

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

• UV Absorption: 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: The charge on histidine varies from +2 to –1 depending on pH; the isoelectric point (pI) is where net charge is zero.

• Posttranslational Modifications: Amino acids can be modified after translation, affecting signaling, calcium binding, structural stability, and gene expression.

• Example: Phosphoserine and 4-hydroxyproline are modified amino acids found in proteins.

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 fundamental to protein biosynthesis.

• Condensation Reaction: The formation of a peptide bond involves the condensation of two amino acids, 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 is characterized by electron delocalization, which imparts planarity and stability to the bond.

• Planar and Stable: Delocalization of electrons between the carbonyl oxygen and amide nitrogen creates a rigid, planar structure.

• Partial Double Bond Character: Restricts rotation around the peptide bond.

Peptide Bond Cleavage

Peptide bonds can be hydrolyzed under specific conditions, either chemically or enzymatically.

• 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.

• Proteases: Enzymes that cleave specific peptide bonds in proteins.

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, D (Glu, Asp)	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 consists of four amino acids linked by peptide bonds.

Important Peptide Regions

Peptides and proteins have distinct regions, including termini and side chains, which influence their structure and function.

• N-terminus: The amino end of the peptide.

• C-terminus: The carboxyl end of the peptide.

• 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: Another common N-terminal modification.

• 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 on a peptide becomes more negative; as pH decreases, it becomes more positive.

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

• Example: Titration curves illustrate the changing charge of peptides with pH.