AbstractIt is generally accepted today that the hydrophobic force is the dominant energetic factor that leads to the folding of polypeptide chains into compact globular entities. This principle was first explicitly introduced to protein chemists in 1938 by Irving Langmuir, past master in the application of hydrophobicity to other problems, and was enthusiastically endorsed by J.D. Bernal. But both proposal and endorsement came in the course of a debate about a quite different structural principle, the so‐called “cyclol hypothesis” proposed by D. Wrinch, which soon proved to be theoretically and experimentally unsupportable. Being a more tangible idea, directly expressed in structural terms, the cyclol hypothesis received more attention than the hydrophobic principle and the latter never actually entered the mainstream of protein science until 1959, when it was thrust into the limelight in a lucid review by W. Kauzmann. A theoretical paper by H.S. Frank and M. Evans, not itself related to protein folding, probably played a major role in the acceptance of the hydrophobicity concept by protein chemists because it provided a crude but tangible picture of the origin of hydrophobicity per se in terms of water structure.

A number of facts relating to proteins suggest that the polypeptides in native protein are in a folded state (Astbury 1933, 1934; Astbury and Street 1930, 1931; Pryde 1931; Wrinch 1936 a , b , c , 1937 a ; Langmuir, Schaefer and Wrinch 1937). The type of folding must be such as to imply the possibility of the regular and orderly arrangement of hundreds 01 amino-acid residues which to some extent at least is independent of the particular residues in question. We propose therefore to formulate all types of folding which are geometrically possible. Each hypothesis in turn can then be tested in two ways. We may consider its plausibility in itself: and having developed its implications to the farthest possible point, we may test it against known facts by ad hoc experiments. At present two types of folding have been suggested—by means of cyclol links (Wrinch 1936 a , b , c , 1937 a ; Langmuir, Schaefer and Wrinch 1937; Astbury 1936 a , b , c ; Frank, 1936) and by means of hydrogen bonds (Jordan Lloyd 1932; Jordan Lloyd and Marriott 1933; Mirsky and Pauling 1936; Wrinch and Jordan Lloyd 1936). The search for other types of folding is being continued. So far it has not proved possible to discard either theory on the grounds that the type of link postulated is out of the question. It is there­ fore very desirable to test these theories by means of their implications. Accordingly, on this occasion we consider (Wrinch 1937 b , c ) whether the cyclol theory can stand the test of the body of facts relating to the “globular” proteins, established by Svedberg and his collaborators (Svedberg and others 1929, 1930 a , b , 1934 a , b , 1935).