ABSTRACT
The classical experiments by Anfinsen and others established that the entire information required for the folding of polypeptide chains to the native three-dimensional conformation is encoded in their primary amino acid sequences (Epstein et al., 1963). This information directs the formation of multiple non-covalent and covalent interactions within polypeptide chains and between subunits of protein oligomers which drive the folding process and stabilize the folded structures (chapter Seckler and Jaenicke). It also establishes a balance between structural stability and flexibility, achieved by low conformational stability of the folded protein (Privalov, 1979), which is required for the folding process itself and the activity of the folded protein. This balance implies that correct and incorrect folding, as well as native and nonnative structures, are separated by only relatively small energy barriers. Subtle changes in the amino acid sequence or the folding milieu may therefore have dramatic consequences for the folding process and the structural integrity of proteins. Misfolding of proteins is indeed the major damaging consequence of stress situations such as heat shock. Misfolded proteins frequently expose hydrophobic surfaces that are prone to intermolecular aggregation, a largely irreversible reaction.
