Amino acids are the molecular building blocks that link together to form proteins; their chemical characteristics determine a protein’s overall shape and function. The defining feature of the 20 common amino acids is the side chain (R group), which dictates how the molecule interacts with its environment. Based on charge and polarity, amino acids are classified as water-loving (hydrophilic) or water-fearing (hydrophobic). Hydrophobic amino acids possess side chains that actively avoid the surrounding aqueous solution, a property that drives major biological processes.
Identifying the Nonpolar Amino Acids
The hydrophobic group contains nine members, characterized by side chains composed mostly of nonpolar carbon and hydrogen atoms. These amino acids are often subcategorized based on the structure of the side chain.
The nine hydrophobic amino acids are:
- Alanine (Ala, A)
- Glycine (Gly, G)
- Isoleucine (Ile, I)
- Leucine (Leu, L)
- Methionine (Met, M)
- Phenylalanine (Phe, F)
- Proline (Pro, P)
- Tryptophan (Trp, W)
- Valine (Val, V)
Aliphatic and Unique Structures
The majority are aliphatic amino acids, meaning their side chains are linear or branched hydrocarbon chains. Alanine has a simple methyl group, while Valine, Leucine, and Isoleucine feature increasingly larger, branched hydrocarbon groups that increase their nonpolar character. Glycine, with only a hydrogen atom as its side chain, is the least hydrophobic due to its minimal size. Methionine is also aliphatic, possessing a sulfur atom embedded within its chain.
Aromatic Amino Acids
A second group consists of the aromatic hydrophobic amino acids, which contain stable, ring-like structures. Phenylalanine is highly hydrophobic, featuring a benzene ring. Tryptophan is the largest amino acid, containing a fused double-ring indole structure that contributes to its strong hydrophobicity. Proline is unique because its side chain loops back to connect with the main amino group, forming a rigid, nonpolar ring that influences protein backbone flexibility.
The Chemistry Behind Water-Fearing Side Chains
The property of hydrophobicity stems from polarity. Water molecules are highly polar, with oxygen atoms attracting electrons more strongly than hydrogen atoms. This polarity allows water molecules to form extensive hydrogen bond networks with each other, creating a highly stable, ordered structure.
Hydrophobic amino acid side chains, in contrast, are nonpolar because they are dominated by carbon-hydrogen (C-H) bonds, where electrons are shared almost equally. These nonpolar surfaces cannot engage in the charged interactions or hydrogen bonding that characterize water’s network. When a nonpolar molecule is introduced into water, the surrounding water molecules are forced to reorganize into a more ordered, cage-like structure, known as a clathrate, around the nonpolar surface.
This forced ordering of water is the basis of the “hydrophobic effect,” a phenomenon driven by thermodynamics. The formation of these ordered cages represents a decrease in the overall system’s disorder, or entropy, which is energetically unfavorable. To minimize this entropic cost, water molecules effectively push the nonpolar side chains together, causing them to aggregate and reduce the total surface area exposed to the water. This tendency to self-associate is a consequence of water maximizing its own hydrogen bonding and disorder.
The quantitative measure of this property is captured by scales like the Kyte-Doolittle hydropathy index, which assigns a numerical value to each amino acid based on its relative hydrophobicity. Positive values on this scale indicate a hydrophobic tendency, reflecting the residue’s preference to reside in a nonpolar environment. This index is derived from factors like the energy required to transfer the side chain from water to an organic solvent. Leucine, Isoleucine, and Phenylalanine consistently receive the highest positive values, confirming their status as the most strongly water-fearing residues.
Role in Protein Folding and Structure
The hydrophobic effect is the most significant driving force in the spontaneous three-dimensional folding of proteins. When a polypeptide chain is synthesized in the aqueous environment of a cell, nonpolar residues move away from the water to minimize the unfavorable entropic penalty. This causes the protein to collapse rapidly into a compact structure, burying its hydrophobic side chains in the interior.
Globular Proteins
In globular proteins, typically found dissolved in the cell’s cytoplasm, the structure features a tightly packed, water-free core composed almost entirely of hydrophobic amino acids. This arrangement shields the residues from the surrounding solvent, stabilizing the protein’s final shape. Conversely, hydrophilic amino acids are predominantly located on the protein’s surface, where they interact with the aqueous environment.
Membrane Proteins
A different structural role emerges for membrane proteins, which are embedded within the nonpolar lipid bilayer of cell membranes. The transmembrane domains are stretches of amino acids highly enriched with hydrophobic residues. Here, the hydrophobic side chains are exposed on the exterior of the protein, interacting favorably with the nonpolar, fatty acid tails of the surrounding lipid molecules. This arrangement allows the protein to be stably anchored within the membrane, facilitating its function.