Protein folding is the process by which a polypeptide chain acquires an organized spatial arrangement. The interactions of its amino acid residues with one another and the surroundings favor some arrangements over others. Protein folding can bring chemically useful groups together at an active site without changing their order along the protein backbone. Its importance is practical: knowing a sequence alone does not tell us whether a sample has the structure needed for function. See Cooper: acquiring functional protein structure.
The ribonuclease A refolding experiment showed that an isolated protein could recover its native properties without a pre-existing folded template under suitable laboratory conditions. Anfinsen interpreted this through a thermodynamic hypothesis: the native arrangement minimizes the whole system's Gibbs free energy in the appropriate environment. His Nobel lecture was delivered on 11 December 1972 and published in Science in 1973. The specified environment is part of the claim, not a disposable qualification. See Anfinsen, Principles that Govern the Folding of Protein Chains, Science 181, 223–230 (1973): Nobel lecture, especially p. 223.
This does not imply that every protein rapidly folds unaided. Molecular chaperones can assist protein folding and reduce protein aggregation; required partners, surroundings and time still matter. Goloubinoff and colleagues' 1989 reconstitution experiments demonstrated assistance from two molecular chaperones and ATP in recovering an active enzyme from unfolded chains. This is experimental evidence that assistance can matter even when the chains already have their specified sequences. See Goloubinoff, Christeller, Gatenby and Lorimer, 1989: chaperone-assisted reconstitution of an active enzyme.
Folding while a chain is being synthesized. Changes in elongation timing can affect the resulting folded and functional fraction.
An inclusion body in recombinant protein production is an insoluble aggregate-rich fraction containing the expressed material. Abundance does not demonstrate native folding; any recovered refolded product needs independent identity, assembly and activity checks.
A representation of which pairs of residues in a protein are in contact. In a lattice model, nonconsecutive residues may count as contacting when their lattice sites are adjacent. Several geometric foldings can have the same contact map, making it useful for compressing an enumeration of self-avoiding walks.
A folding funnel is a schematic energy landscape in which increasingly native-like protein conformations tend to have lower free energy, while the many unfolded conformations occupy a broad region. Roughness represents barriers and possible kinetic traps. The funnel is an organizing description, not a claim that every protein follows one unique geometrical trajectory or possesses a rigid isolated native state.
Conformational entropy measures the multiplicity of molecular conformations compatible with specified macroscopic constraints. For equally weighted accessible conformations it is ; for probabilities , it is . A folded protein generally has less chain conformational entropy than its unfolded ensemble, but folding can still lower total Gibbs free energy when solvent and interaction contributions are included.
A molecular chaperone is a protein that assists other proteins in reaching or maintaining useful arrangements, for example by limiting unwanted association during protein folding. Assistance does not rewrite the client's protein primary structure. In a crowded cytoplasm, reducing protein aggregation can make successful protein folding more reliable. See Cooper: molecular chaperones and folding assistance.
