Summary
The 20 standard amino acids are distinguished by their side chains (R groups), which determine protein structure, function, and interactions. Side chains vary in size, charge, hydrophobicity, and chemical reactivity, enabling the vast diversity of protein properties.
Key Points
- 1Side chains determine protein structure, function, and interactions
- 2Classified by polarity: nonpolar, polar, acidic, and basic
- 3Ionization states depend on pKa and local environment
- 4Key roles in catalysis, PTMs, and structural stabilization
The side chain is what makes each amino acid unique, providing the chemical diversity that enables proteins to perform their remarkable range of functions.
Classification of Side Chains
Nonpolar (Hydrophobic) Amino Acids
These residues tend to cluster in protein interiors:
#### Aliphatic Side Chains
- Glycine (Gly, G): H only; maximum conformational flexibility
- Alanine (Ala, A): -CH₃; small, hydrophobic
- Valine (Val, V): Branched -CH(CH₃)₂; β-branched
- Leucine (Leu, L): -CH₂CH(CH₃)₂; most common in proteins
- Isoleucine (Ile, I): β-branched, chiral at Cβ
#### Aromatic Side Chains
- Phenylalanine (Phe, F): Benzyl group; strongly hydrophobic
- Tryptophan (Trp, W): Indole ring; largest amino acid, UV absorbance at 280 nm
- Tyrosine (Tyr, Y): Hydroxyphenyl; can ionize (pKa ~10), phosphorylation site
#### Sulfur-Containing
- Methionine (Met, M): Thioether; initiator codon, oxidation-sensitive
- Cysteine (Cys, C): Thiol (-SH); forms disulfide bonds, highly reactive
#### Cyclic
- Proline (Pro, P): Pyrrolidine ring; restricts backbone, disrupts helices
Polar Uncharged Amino Acids
Capable of hydrogen bonding:
- Serine (Ser, S): -CH₂OH; phosphorylation site, nucleophile
- Threonine (Thr, T): -CH(OH)CH₃; β-branched, phosphorylation site
- Asparagine (Asn, N): -CH₂CONH₂; N-glycosylation site, deamidation-prone
- Glutamine (Gln, Q): -CH₂CH₂CONH₂; deamidation-prone
Charged Amino Acids
#### Positively Charged (Basic)
- Lysine (Lys, K): ε-amino group (pKa ~10.5); PTM sites (acetylation, methylation, ubiquitination)
- Arginine (Arg, R): Guanidinium group (pKa ~12.5); always charged at physiological pH
- Histidine (His, H): Imidazole (pKa ~6); protonation state changes near neutral pH, catalytic residue
#### Negatively Charged (Acidic)
- Aspartate (Asp, D): -CH₂COO⁻ (pKa ~3.9); metal coordination, catalysis
- Glutamate (Glu, E): -CH₂CH₂COO⁻ (pKa ~4.1); neurotransmitter precursor
Chemical Properties
Hydrophobicity Scales
Various scales quantify amino acid hydrophobicity:
- Kyte-Doolittle: Based on water-vapor transfer
- Eisenberg: Consensus scale
- Wimley-White: Interface and octanol scales
Hydrophobicity drives:
Ionization and pKa
Side chain ionization affects protein function:
| Residue | pKa (typical) |
|---------|---------------|
| Asp | 3.9 |
| Glu | 4.1 |
| His | 6.0 |
| Cys | 8.3 |
| Tyr | 10.1 |
| Lys | 10.5 |
| Arg | 12.5 |
Note: Actual pKa values depend on local environment (can shift by several pH units).
Reactivity
#### Nucleophilic Side Chains
Important in enzyme catalysis:
- Serine: Serine proteases, esterases
- Cysteine: Cysteine proteases, thiol chemistry
- Histidine: Acid-base catalysis, metal coordination
- Lysine: Schiff base formation
#### Oxidation-Sensitive
- Cysteine: Disulfides, sulfenic acid, sulfinic acid
- Methionine: Methionine sulfoxide
- Tryptophan: Various oxidation products
- Tyrosine: Radical chemistry
Functional Roles
Enzyme Active Sites
Catalytic residues often include:
- Catalytic triad: Ser-His-Asp (serine proteases)
- Metal coordination: His, Cys, Asp, Glu
- Acid-base catalysis: His, Glu, Asp
Post-Translational Modification Sites
Side chains are targets for PTMs:
- Phosphorylation: Ser, Thr, Tyr
- Glycosylation: Asn (N-linked), Ser/Thr (O-linked)
- Acetylation/Methylation: Lys
- Ubiquitination: Lys
Structural Roles
- Salt bridges: Lys-Asp, Arg-Glu pairs
- Disulfide bonds: Cys-Cys (stabilize tertiary/quaternary structure)
- Aromatic stacking: Phe, Tyr, Trp π-π interactions
- Cation-π interactions: Arg/Lys with aromatics
Special Cases
Selenocysteine (Sec, U)
The "21st amino acid":
Pyrrolysine (Pyl, O)
The "22nd amino acid":