How do proteins acquire their three-dimensional structure and stability?

Proteins are multifunctional in the sense that their specific amino acid sequence simultaneously determines self-organization, function and turnover. Correspondingly, evolution has to compromise between rigidity (stability) and flexibility (function/degradation) to the effect that the free energy of stabilization of proteins is the equivalent of only a few weak interactions (delta Gstab = 45 +/- 15 kJ.mol-1). Molecular adaptation of thermophiles, psychrophiles and other extremophiles is accomplished by extrinsic factors that are not encoded in the amino acid sequence, or by minute local structural changes involving mainly ion pairs and hydrophobic side chains. The acquisition of the native three-dimensional structure may be described by single- or multiple-pathway folding and association, where the fast collapse of the polypeptide chain leads to molten-globule-like states; subsequent shuffling reactions yield structured monomers which, in the case of oligomers, undergo specific association to form the native functional state. The rate-limiting steps (cysteine oxidation, proline isomerization, subunit assembly) are catalyzed or directed by enzymes or chaperones.