The amino acid sequence (primary structure) of a protein determines how it forms its secondary, tertiary, and quaternary structures. For about 75% of proteins, the folding process takes place within milliseconds as the molecule is synthesized. Some proteins fold more slowly, however, and for these molecules folding is a dangerous business. The longer these polypeptides remain in a denatured (unfolded) state, the longer their hydrophobic groups are exposed to other macromolecules in the crowded cytoplasm. The hydrophobic effect, along with van der Waals interactions, tends to bring the exposed hydrophobic groups together, and their inappropriate aggregation may prevent proper folding. Correctly folded proteins can sometimes unfold because of elevated temperature, for example, and in the denatured state they are subject to the same risks of aggregation.

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Cells have evolved proteins called chaperones that help protect slow-folding or denatured proteins until they can attain their proper three-dimensional structure. Chaperones bind with hydrophobic groups and nonpolar R groups to shield them from inappropriate aggregation, and in repeated cycles of binding and release they give the polypeptide time to find its correct shape.