A protein folds into its working shape through hydrogen bonds, ionic attractions, and hydrophobic interactions between amino acid side chains, not through its main chain of peptide bonds. Denaturation breaks these weak, non-covalent forces while leaving the peptide bonds, and therefore the amino acid sequence, completely intact.
Common causes include high heat, strong acids or bases, chaotropic chemicals like urea, organic solvents, and heavy metal ions. Once unfolded, a protein often exposes hydrophobic side chains that were previously tucked inside its core. These exposed regions tend to stick to other unfolded proteins, causing the molecules to clump together, or aggregate.
Because a protein’s function usually depends on its precise three-dimensional shape, denaturation destroys activities such as enzyme catalysis. Under mild conditions, some small proteins can refold correctly if the denaturing agent is removed slowly, a process called renaturation. Many proteins, however, aggregate permanently and cannot recover their original shape or function once denatured.
Cells normally use molecules called chaperones to help proteins fold correctly and to prevent unwanted denaturation under everyday stress.