Structure and Properties of Amino Acids

Learning Outcomes

• Distinguish between L- and D- amino acids.

• Recall the names, three-letter codes, and single-letter codes of all naturally occurring amino acids.

• Recognize the 20 naturally occurring L-amino acids and their structures.

• Describe the importance of amino acid modifications.

• Identify chemical properties of amino acids: acid/base chemistry, hydrophobicity, hydrophilicity, hydrogen bonding, nucleophilicity, and electrophilicity.

• Interpret amino acid titration curves and calculate pI values given pKa values.

Proteins: Amino Acids and Chirality

Biological Macromolecules

Proteins are one of the four major classes of biological macromolecules, alongside nucleic acids, carbohydrates, and lipids. Each class is composed of specific monomeric units:

• Proteins: amino acids

• Nucleic acids: nucleotides

• Carbohydrates: sugars

• Lipids: acetate (fatty acids)

All biological macromolecules share these features:

• Three-dimensional structures (difficult to visualize in 2D)

• Structure is critical to function

• Flexibility allows interaction with other biomolecules

• Dynamic nature: shape changes in response to environment, modifications, and ligand interactions

Functions of Proteins

• Enzymes: Catalyze biochemical reactions

• Storage and transport of molecules

• Membrane channels for transport

• Structural components of cells, organelles, and tissues

• Mechanical motors for movement

• Regulators of gene expression (transcription, translation, replication)

• Receptors for cell signaling and communication

• Specialized functions: antibodies, hormones

Structure of Amino Acids

General Structure

The monomeric unit of proteins is the amino acid. Each amino acid contains:

• An amino group ( or )

• A carboxyl group ( or )

• A side chain (R group) unique to each amino acid

• A central alpha carbon (C_\alpha)

At physiological pH (~7), amino acids exist primarily as zwitterions, carrying both positive and negative charges but with a net zero charge:

• Amino group: weak base,

• Carboxyl group: weak acid,

Zwitterion formation:

• At low pH: amino group is protonated (), carboxyl group is protonated ()

• At neutral pH: amino group is protonated (), carboxyl group is deprotonated ()

• At high pH: amino group is deprotonated (), carboxyl group is deprotonated ()

Chirality and Stereochemistry

The alpha carbon (C_\alpha) of amino acids (except glycine) is chiral, attached to four different substituents:

• Amino group

• Carboxyl group

• Hydrogen atom

• R group (side chain)

This chirality leads to two possible enantiomers (stereoisomers): L- and D- forms. In biological systems, only L-amino acids are incorporated into proteins.

Fischer projection: Used to distinguish L- and D- forms. L-amino acids have the R group on the left when the amino group is at the top and the carboxyl group at the bottom.

Mnemonic: The CORN rule (COOH, R, NH2) in a clockwise direction when viewed from the hydrogen atom indicates the L-configuration.

R,S System

The R,S system assigns priorities to substituents based on atomic number. The configuration is determined by the order of the three highest priority groups when viewed from the lowest priority group:

• Clockwise: R

• Counterclockwise: S

Note: The R/S system is independent of optical activity and the L/D system.

Classification of Amino Acids

Categories Based on Side Chains

The 20 naturally occurring amino acids are classified by the properties of their side chains:

• Hydrophobic (non-polar): Gly, Ala, Val, Leu, Ile, Met, Pro

• Polar (uncharged): Ser, Thr, Cys, Gln, Asn

• Charged: Asp, Glu (negative); Lys, Arg, His (positive)

• Aromatic: Phe, Tyr, Trp

Side chains determine the physical and chemical character of each amino acid and the proteins they form.

Structural Features

• Proline: Only cyclic amino acid; often found in cis peptide bonds.

• Aromatic amino acids: Phenylalanine (Phe), Tyrosine (Tyr), Tryptophan (Trp); absorb UV light at 280 nm.

• Glycine: No side chain; not chiral; highly flexible.

• Methionine: Contains sulfur; hydrophobic.

Chemical Properties of Amino Acids

Acid/Base Chemistry

Amino acids can act as acids or bases depending on the pH of the environment. The ionization state affects their charge and reactivity.

• Acidic amino acids: Aspartate (Asp), Glutamate (Glu); side chain carboxyl group,

• Basic amino acids: Lysine (Lys), Arginine (Arg), Histidine (His); side chain amino or imidazole group, varies

Hydrophobicity and Hydrophilicity

• Hydrophobic amino acids: Non-polar side chains; found in protein interiors.

• Hydrophilic amino acids: Polar or charged side chains; found on protein surfaces.

Hydrogen Bonding

• Amides: Asparagine (Asn), Glutamine (Gln); side chains can donate and accept hydrogen bonds.

• Hydroxyls: Serine (Ser), Threonine (Thr); can form hydrogen bonds and act as nucleophiles when deprotonated.

Nucleophilicity and Electrophilicity

• Nucleophiles: Electron donors; Lys, Arg, His, Cys, Ser, Thr, Asp, Glu

• Electrophiles: Electron acceptors; less common among amino acids

Cysteine can form disulfide bonds, important for protein structure:

• Occurs in oxidizing environments (e.g., extracellular space, ER)

• Disulfide bond formation:

Post-Translational Modifications

Amino acids in proteins can be chemically modified after translation, increasing functional diversity:

• Phosphorylation: Addition of phosphate (e.g., phosphoserine)

• Hydroxylation: Addition of hydroxyl group (e.g., 4-hydroxyproline)

• Acetylation: Addition of acetyl group (e.g., N-e-acetyllysine)

• Carboxylation: Addition of carboxyl group (e.g., γ-carboxyglutamate)

Amino Acid Titration Curves and pI Calculation

Titration Curves

Titration curves show how the charge of an amino acid changes with pH. Key features include:

• pKa values for ionizable groups

• Isoelectric point (pI): pH at which net charge is zero

For glycine:

• (carboxyl group)

• (amino group)

For amino acids with ionizable side chains, the pI is calculated using the two pKa values that correspond to the neutral species.

Buffering Regions

• Best buffering occurs near the pKa values.

• At pH values near pKa, the amino acid can resist changes in pH.

Table: Classification of Amino Acids by Side Chain Properties

Key Equations

• Isoelectric point (pI) for amino acids without ionizable side chains:

• Beer-Lambert Law (for protein concentration):

• Where = absorbance, = molar absorptivity, = concentration, = path length

Summary

• Amino acids are the building blocks of proteins, each with unique side chains that determine their chemical and physical properties.

• Understanding stereochemistry, classification, and titration behavior is essential for studying protein structure and function.

• Post-translational modifications and side chain reactivity expand the functional repertoire of proteins in biological systems.

Additional info: Some details on mnemonic devices, post-translational modifications, and the Beer-Lambert law were inferred and expanded for completeness.