Cyclol

The cyclol hypothesis is the now discredited first structural model of a folded, globular protein, formulated in the 1930s.^[1] It was based on the cyclol reaction of peptide bonds proposed by physicist Frederick Frank in 1936,^[2] in which two peptide groups are chemically crosslinked. These crosslinks are covalent analogs of the non-covalent hydrogen bonds between peptide groups and have been observed in rare cases, such as the ergopeptides.

Based on this reaction, mathematician Dorothy Wrinch hypothesized in a series of five papers in the late 1930s a structural model of globular proteins. She postulated that, under some conditions, amino acids will spontaneously make the maximum possible number of cyclol crosslinks, resulting in cyclol molecules and cyclol fabrics. She further proposed that globular proteins have a tertiary structure corresponding to Platonic solids and semiregular polyhedra formed of cyclol fabrics with no free edges. In contrast to the cyclol reaction itself, these hypothetical molecules, fabrics and polyhedra have not been observed experimentally. The model has several consequences that render it energetically implausible, such as steric clashes between the protein sidechains. In response to such criticisms J. D. Bernal proposed that hydrophobic interactions are chiefly responsible for protein folding,^[3] which was indeed borne out.