Kaplan ch 1

Amino Acids, Peptides, and Proteins

Introduction

Amino acids, peptides, and proteins are fundamental biomolecules that play critical roles in biological systems. Their structure and properties determine the function of enzymes, structural components, and signaling molecules in living organisms.

1.1 Amino Acids Found in Proteins

A Note on Terminology

• Amino acids are organic compounds containing both an amino group (-NH2) and a carboxylic acid group (-COOH) attached to a central (α) carbon.

• In proteins, the amino and carboxyl groups are bonded to the same α-carbon.

• Only the 20 proteinogenic amino acids encoded by the genetic code are typically considered in biochemistry.

• Some amino acids are modified for specialized functions (e.g., ornithine in the urea cycle).

Stereochemistry of Amino Acids

• Most amino acids are chiral (optically active), except glycine, which has two hydrogen atoms attached to the α-carbon.

• In eukaryotes, amino acids are in the L-configuration (Fischer projection: amino group on the left).

• All chiral amino acids except cysteine have an S configuration.

Structures of the Amino Acids

• Each amino acid has a unique R group (side chain) that determines its chemical properties and function.

• Side chains can be classified as nonpolar, polar, aromatic, acidic, or basic.

Hydrophobic and Hydrophilic Amino Acids

• Hydrophobic amino acids (e.g., glycine, alanine, valine, leucine, isoleucine, methionine, proline, phenylalanine, tryptophan) tend to be buried within protein structures, away from water.

• Hydrophilic amino acids (e.g., serine, threonine, asparagine, glutamine, cysteine, aspartate, glutamate, lysine, arginine, histidine) are often found on protein surfaces, interacting with the aqueous environment.

Amino Acid Abbreviations

• Amino acids are identified by their full name, three-letter abbreviation, and one-letter code (e.g., Glycine: Gly, G).

1.2 Acid-Base Chemistry of Amino Acids

Protonation and Deprotonation

• Amino acids are amphoteric: they can act as both acids and bases.

• They have at least two ionizable groups (amino and carboxyl), each with a characteristic pKa value.

• At low pH, amino acids are fully protonated; at high pH, they are fully deprotonated.

• The isoelectric point (pI) is the pH at which the amino acid has no net charge.

Equation for pI (uncharged side chain):

$pI = \frac{pK_{a,\text{amino}} + pK_{a,\text{carboxyl}}}{2}$

Equation for pI (acidic side chain):

$pI = \frac{pK_{a,\text{R group}} + pK_{a,\text{carboxyl}}}{2}$

Equation for pI (basic side chain):

$pI = \frac{pK_{a,\text{R group}} + pK_{a,\text{amino}}}{2}$

Titration of Amino Acids

• Titration curves of amino acids show buffering regions at each pKa value.

• Amino acids with charged side chains have three pKa values and more complex titration curves.

1.3 Peptide Bond Formation and Hydrolysis

Peptide Bond Formation

• Peptide bonds are specialized amide bonds formed between the carboxyl group of one amino acid and the amino group of another.

• Formation is a condensation (dehydration) reaction, releasing a molecule of water.

• Peptide bond formation can also be viewed as an acyl substitution reaction.

General reaction:

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

Peptide Bond Hydrolysis

• Hydrolysis of peptide bonds is catalyzed by specific enzymes (e.g., trypsin, chymotrypsin).

• Hydrolysis adds a hydrogen atom to the amide nitrogen and a hydroxyl group to the carbonyl carbon.

1.4 Primary and Secondary Protein Structure

Primary Structure

• The primary structure is the linear sequence of amino acids in a polypeptide, stabilized by peptide bonds.

• Primary structure determines all higher levels of protein structure.

• Sequencing techniques can determine the primary structure from DNA or protein samples.

Secondary Structure

• Secondary structure refers to local folding patterns stabilized by hydrogen bonds between backbone atoms.

• Common types: α-helix (right-handed coil stabilized by hydrogen bonds every four residues) and β-pleated sheet (extended strands connected by hydrogen bonds).

• Proline often disrupts secondary structure due to its rigid cyclic structure.

1.5 Tertiary and Quaternary Protein Structure

Tertiary Structure

• Tertiary structure is the three-dimensional shape of a single polypeptide chain.

• Stabilized by hydrophobic interactions, hydrogen bonds, ionic interactions, and disulfide bridges (covalent bonds between cysteine residues).

• Hydrophobic residues are typically buried in the protein core, while hydrophilic residues are exposed to solvent.

Folding and the Solvation Layer

• Protein folding is driven by the hydrophobic effect, which increases the entropy of surrounding water molecules.

• Hydrophobic residues cluster away from water, while hydrophilic residues interact with the solvent.

Quaternary Structure

• Quaternary structure exists in proteins with multiple polypeptide chains (subunits).

• Provides stability, reduces DNA needed for encoding, brings catalytic sites together, and allows for cooperative/allosteric effects.

Conjugated Proteins

• Conjugated proteins contain covalently attached prosthetic groups (e.g., heme, carbohydrates, lipids).

• Prosthetic groups can determine protein function and localization.

1.6 Denaturation

Denaturation of Proteins

• Denaturation is the loss of a protein's three-dimensional structure and function due to disruption of noncovalent interactions and disulfide bonds.

• Caused by heat, chemicals (e.g., urea, detergents), or extreme pH.

• Denaturation is often irreversible, as seen when cooking egg whites.

Concept Summary Table: Amino Acid Classification

Type	Amino Acids	Properties
Nonpolar, Nonaromatic	Glycine, Alanine, Valine, Leucine, Isoleucine, Methionine, Proline	Hydrophobic, found in protein interiors
Aromatic	Phenylalanine, Tyrosine, Tryptophan	Hydrophobic, absorb UV light
Polar, Uncharged	Serine, Threonine, Asparagine, Glutamine, Cysteine	Hydrophilic, often on protein surfaces
Acidic (Negatively Charged)	Aspartate, Glutamate	Hydrophilic, negatively charged at physiological pH
Basic (Positively Charged)	Lysine, Arginine, Histidine	Hydrophilic, positively charged at physiological pH

Sample MCAT-Style Questions (with Answers)

• 1. In a neutral solution, most amino acids exist as: Answer: B. Zwitterions

• 2. At pH 7, the charge on a glutamic acid molecule is: Answer: B. -1

• 3. Nonpolar R groups in aqueous solution: Answer: C. They are hydrophobic and found buried within proteins.

• 4. cDNA sequence and protein structure: Answer: A. Primary structure

• 5. Number of distinct tripeptides from valine, alanine, leucine: Answer: C. 6

• 6. Entropy change during protein folding: Answer: B. Entropy of the water increases; entropy of the protein decreases.

• 7. α-helix stabilization: Answer: C. Hydrogen bonds

• 8. Least likely to cause denaturation: Answer: C. Moving to a more hypotonic environment

• 9. Amino acid in transmembrane α-helix: Answer: C. Phenylalanine

• 10. Amino acids with chiral carbon in side chain: Answer: C. II and III only (Threonine and Isoleucine)

• 11. Protein structure change upon dimerization: Answer: B. Tertiary to quaternary

• 12. Amino acid with ionizable side chain: Answer: A. Histidine

• 13. pI of lysine: Answer: D. 9.8

• 14. Reason for conjugating proteins: Answer: D. I, II, and III (multiple reasons)

• 15. Amino acid in collagen: Answer: B. Glycine

Key Equations

• Isoelectric point (pI) for neutral amino acid: $pI = \frac{pK_{a,\text{amino}} + pK_{a,\text{carboxyl}}}{2}$

• Isoelectric point (pI) for acidic amino acid: $pI = \frac{pK_{a,\text{R group}} + pK_{a,\text{carboxyl}}}{2}$

• Isoelectric point (pI) for basic amino acid: $pI = \frac{pK_{a,\text{R group}} + pK_{a,\text{amino}}}{2}$

Summary

• Amino acids are the building blocks of proteins, with diverse chemical properties determined by their side chains.

• Proteins have hierarchical structures: primary (sequence), secondary (local folding), tertiary (3D shape), and quaternary (multi-subunit complexes).

• Protein function depends on structure, which is sensitive to environmental conditions and chemical modifications.