A polypeptide's tertiary structure is its overall three-dimensional fold: the way its helices, sheets, loops and side chains pack together in one chain. If a functional protein contains several polypeptide chains, their arrangement is its quaternary structure.

Protein folding is stabilized by many ordinary chemical interactions acting together rather than by one special 'protein force.' Important contributions include:

• the hydrophobic effect, which often favors burial of nonpolar side chains away from water;
• hydrogen bonds among polar groups;
• electrostatic attractions and repulsions among charged groups;
• van der Waals contacts created by close packing;
• covalent disulfide bonds, S-S linkages that can connect two cysteine side chains in some proteins.

The relative importance of these contributions depends on the protein and its environment.

Sequence constrains structure

The amino-acid sequence determines where different side-chain chemistries occur along the chain. A segment rich in nonpolar residues may become buried in a soluble protein or become compatible with the nonpolar interior of a membrane. Charged and polar groups may remain solvent-exposed or form specific internal interactions.

Folding is therefore not equivalent to simply 'making the molecule compact.' A functional fold must satisfy many local geometric and chemical constraints simultaneously.

Quaternary assembly

Different polypeptide chains can associate through the same noncovalent forces used within one folded chain. Hemoglobin, for example, functions as an assembly of several subunits. Each subunit has its own tertiary structure, while the arrangement of subunits is quaternary structure.

Not every protein has quaternary structure: a single-chain protein can function without assembling with another polypeptide.

Denaturation

Denaturation is loss of the native higher-order structure without necessarily breaking the peptide backbone. Heat, extreme pH, organic solvents or detergents can disrupt the interaction balance that stabilizes a fold.

A denatured protein may lose biological function because binding and catalysis depend on three-dimensional arrangement, even though its primary sequence remains intact.

Some proteins can refold when normal conditions are restored; others aggregate or remain trapped in long-lived non-native structures. A favorable native structure therefore does not imply that every polypeptide reaches it instantly or reversibly under every condition.

The central principle is that protein function depends on structure, and structure emerges from sequence interacting with the surrounding chemical environment.