🧬 Chemical Properties of Polypeptides — Full Study Summary

🌱 Why Polypeptide Chemistry Matters (Intro)

Virtually all biological function depends on proteins, and protein function is inseparable from chemical structure. Proteins:

• Are linear polymers of amino acids
• Fold into precise 3D structures
• Perform catalysis, transport, signaling, structural support, and regulation

To understand proteins, we must first understand:

• Amino acid chemistry
• Peptide bond formation
• Side-chain reactivity
• How chemical properties affect folding and function

1.1 🧱 The Polymeric Nature of Proteins

Proteins are heteropolymers

• Built from 20 standard amino acids
• Amino acids differ only in side chains (R groups)
• Sequence order determines structure → function

General amino acid structure

Each amino acid contains:

• α-carbon (chiral except Gly)
• Amino group (–NH₂ / –NH₃⁺)
• Carboxyl group (–COOH / –COO⁻)
• Side chain (R)

⚠️ All protein amino acids are L-isomers

Naming conventions

• Full name (e.g., Alanine)
• 3-letter code (Ala)
• 1-letter code (A)

Peptides vs proteins

• Peptide: short chain, undefined structure
• Polypeptide: longer chain
• Protein: folded, biologically active polypeptide

1.2 🔗 The Polypeptide Backbone

Peptide bond formation

• Condensation reaction between:
  • α-carboxyl of one amino acid
  • α-amino of next amino acid
• Releases H₂O
• Forms planar amide (peptide) bond

Peptide bond properties

• Partial double-bond character
• Restricted rotation
• Usually trans configuration

Backbone geometry

Each residue contributes:

• φ (phi) angle: rotation around N–Cα
• ψ (psi) angle: rotation around Cα–C
• ω (peptide bond): usually fixed

➡️ These angles define secondary structure

1.3 🧪 Amino Acid Residues (Main Chapter)

This section analyzes each side-chain class, focusing on:

• Structure
• Ionization
• Chemical reactivity
• Experimental modification

1.3.1 Glycine (Gly)

• Side chain = H
• Achiral
• Extremely flexible
• Common in turns and tight regions
• Destabilizes rigid secondary structure

1.3.2 Aliphatic Residues (Ala, Val, Leu, Ile)

• Nonpolar, hydrophobic
• Drive hydrophobic collapse
• Usually buried inside proteins
• Poor hydrogen bonding

1.3.3 Proline — the Cyclic Imino Acid 🌀

• Side chain bonds to backbone N
• Rigid structure
• No backbone NH for H-bonding
• Breaks α-helices
• Often found in turns

1.3.4 Hydroxyl Residues: Ser & Thr

• Polar, uncharged
• Can form hydrogen bonds
• OH group:
  • Weakly nucleophilic
  • Target for phosphorylation
• Thr is bulkier → more steric constraint

1.3.5 Acidic Residues: Asp & Glu

• Side chains contain carboxyl groups
• Negatively charged at physiological pH
• Participate in:
  • Salt bridges
  • Metal binding
  • Acid–base catalysis

⚠️ Can form cyclic anhydrides under special conditions

1.3.6 Amide Residues: Asn & Gln

• Derived from Asp/Glu
• Polar but uncharged
• Strong hydrogen bonding
• Susceptible to deamidation
  • Alters protein stability and function

1.3.7 Basic Residues: Lys & Arg

Lysine (Lys)

• ε-amino group
• Positively charged
• Highly reactive:
  • Acylation
  • Alkylation
  • Schiff base formation
• Frequently chemically modified in experiments

Arginine (Arg)

• Guanidinium group
• Always positively charged
• Less reactive than Lys
• Strong electrostatic interactions

1.3.8 Histidine (His) ⚖️

• Imidazole side chain
• pKa ≈ physiological pH
• Can be protonated or neutral
• Ideal for:
  • Enzyme active sites
  • Proton transfer
• Exhibits tautomerism

1.3.9 Aromatic Residues: Phe, Tyr, Trp 🌈

Phenylalanine (Phe)

• Hydrophobic
• Minimal chemical reactivity

Tyrosine (Tyr)

• Phenolic OH
• Can be ionized
• Undergoes:
  • Nitration
  • Iodination
  • Phosphorylation
• Strong UV absorbance

Tryptophan (Trp)

• Indole ring
• Most UV-active residue
• Strong intrinsic fluorescence
• Sensitive to environment → folding probe

📊 UV spectra figure shows distinct absorbance peaks for Phe, Tyr, Trp

1.3.10 Sulfur-Containing Residues: Met & Cys 🧷

Methionine (Met)

• Thioether
• Hydrophobic
• Can be oxidized (Met → Met-O)

Cysteine (Cys)

• Thiol group (–SH)
• Highly reactive
• Can:
  • Form disulfide bonds
  • Bind metals
  • Undergo oxidation/reduction

Disulfide chemistry

• Cys–Cys → disulfide bond
• Stabilizes extracellular proteins
• Reversible via reducing agents (DTT, β-ME)

⚠️ Disulfide exchange reactions are kinetically controlled

1.4 🔍 Detection of Amino Acids & Proteins (Start)

• Protein studies require quantification
• UV absorbance (especially Tyr/Trp) commonly used
• Sensitivity depends on:
  • Amino acid composition
  • Protein environment
• Chemical labeling reagents exploit side-chain reactivity

(This section continues beyond p. 20)

🧠 Key Takeaways (Exam Gold)

• Side chains define protein chemistry
• Backbone is structurally constrained
• Reactivity ≠ abundance
• Histidine is chemically unique
• Cysteine chemistry underlies redox regulation
• Aromatic residues enable spectroscopic detection