In Levels of Protein Structure you saw that R groups shape the tertiary fold. All 20 amino acids share the same backbone; they differ only in the R group (side chain). For predicting folds, sort the R groups into four families by how they behave in water.
| Family | What the R group has | Examples (R group) |
|---|---|---|
| Nonpolar (hydrophobic) | Mostly C and H; no charge | alanine –CH₃, valine, leucine, phenylalanine (a benzene ring) |
| Polar, uncharged | An –OH or an amide (–CONH₂) that can hydrogen-bond | serine –CH₂OH, threonine, asparagine, glutamine |
| Acidic (negative) | A carboxyl group, –COO⁻ at cell pH | aspartic acid –CH₂COO⁻, glutamic acid |
| Basic (positive) | An amino group, –NH₃⁺ at cell pH | lysine –(CH₂)₄NH₃⁺, arginine |
Key idea
In a protein dissolved in water, nonpolar R groups cluster inside the fold, away from water, and polar and charged R groups sit on the surface, touching water. A swap that keeps the family usually changes little. A swap that puts a charge where a nonpolar group belongs, or the reverse, can wreck the fold.
Why it works
Water molecules hydrogen-bond to each other and to anything polar or charged. Nonpolar side chains cannot join in, so water around them is forced into a more ordered cage. Folding so those side chains hide together frees the water. That is the hydrophobic effect, the biggest single force in folding. Charged R groups, by contrast, are surrounded happily by water, and opposite charges inside a fold can pair as ionic bonds.
Worked examples
Worked example: A swap inside the fold
A leucine buried in the core of an enzyme is replaced by isoleucine in one mutant and by aspartic acid in another. Which mutant is more likely to lose its shape?
- Leucine and isoleucine are both nonpolar, with the same atoms arranged a little differently.
- Aspartic acid carries a negative charge.
- A charge buried in the oily core is not surrounded by water; the fold must change to let it reach water.
Answer: The aspartic acid mutant. Leucine to isoleucine usually changes very little.
Worked example: A swap on the surface: sickle-cell hemoglobin
In sickle-cell hemoglobin, the sixth amino acid of the β chain changes from glutamic acid to valine. The changed spot is on the surface. Why does that matter?
- Glutamic acid is acidic (charged) and sits happily in water on the surface.
- Valine is nonpolar.
- A nonpolar patch on the surface sticks to nonpolar patches on other hemoglobin molecules, so when oxygen is low they link into long fibers.
Answer: One charged R group became a nonpolar one on the surface, making the molecules stick together.
Common mistake
Assuming any change of one amino acid ruins a protein. Many swaps, especially within a family or at positions that do not touch the active site, change little; that is why related species can have slightly different versions of the same working protein. What to check: the family of the old and new R group, and where the position sits (inside, surface, active site).