page_title: Cyclol
section_title: Basic theory
hierarchical_section_title: Cyclol / Basic theory
caption_attribution_description: "Stick" image of the cyclol-6 molecule proposed by Dorothy Maud Wrinch in 1936 (Nature, 137, 411-412). This molecule can be considered a cyclic hexapeptide in which three peptide groups have fused by cyclol reactions into a central ring. Note that the three outer (unfused) peptide groups are not planar, but have dihedral angle ω=60°. The three red atoms in the central ring represent the hydroxyl groups formed by the cyclol reactions, whereas the three outer red atoms represent the oxygens of carbonyl groups. The PDB file was constructed by me using my own software and visualized using PyMol; both were done on 20 October 2006. I hereby release this image under the GFDL.
context_page_description: The cyclol hypothesis is the first structural model of a folded, globular protein. It was developed by Dorothy Wrinch in the late 1930s, and was based on three assumptions. Firstly, the hypothesis assumes that two peptide groups can be crosslinked by a cyclol reaction; these crosslinks are covalent analogs of non-covalent hydrogen bonds between peptide groups. These reactions have been observed in the ergopeptides and other compounds. Secondly, it assumes that, under some conditions, amino acids will naturally make the maximum possible number of cyclol crosslinks, resulting in cyclol molecules and cyclol fabrics. These cyclol molecules and fabrics have never been observed. Finally, the hypothesis assumes that globular proteins have a tertiary structure corresponding to Platonic solids and semiregular polyhedra formed of cyclol fabrics with no free edges. Such "closed cyclol" molecules have not been observed either.
context_section_description: Wrinch developed this suggestion into a full-fledged model of protein structure.  The basic cyclol model was laid out in her first paper (1936).  She noted the possibility that polypeptides might cyclize to form closed rings (true) and that these rings might form internal crosslinks through the cyclol reaction (also true, although rare).  Assuming that the cyclol form of the peptide bond could be more stable than the amide form, Wrinch concluded that certain cyclic peptides would naturally make the maximal number of cyclol bonds (such as cyclol 6, Figure 2).  Such cyclol molecules would have hexagonal symmetry, if the chemical bonds were taken as having the same length, roughly 1.5 Å; for comparison, the N-C and C-C bonds have the lengths 1.42 Å and 1.54 Å, respectively.
  These rings can be extended indefinitely to form a cyclol fabric (Figure 3).  Such fabrics exhibit a long-range, quasi-crystalline order that Wrinch felt was likely in proteins, since they must pack hundreds of residues densely.  Another interesting feature of such molecules and fabrics is that their amino-acid side chains point axially upwards from only one face; the opposite face has no side chains.  Thus, one face is completely independent of the primary sequence of the peptide, which Wrinch conjectured might account for sequence-independent properties of proteins.
  In her initial article, Wrinch stated clearly that the cyclol model was merely a working hypothesis, a potentially valid model of proteins that would have to be checked.  Her goals in this article and its successors were to propose a well-defined testable model, to work out the consequences of its assumptions and to make predictions that could be tested experimentally.  In these goals, she succeeded; however, within a few years, experiments and further modeling showed that the cyclol hypothesis was untenable as a model for globular proteins.
caption: Figure 2: The alanine cyclol-6 molecule proposed by Dorothy Wrinch is a cyclic hexapeptide in which three peptide groups are fused by cyclol reactions into a central ring.  The three outer (unfused) peptide groups are not planar, but have dihedral angle ω=60°.  The three red atoms in the central ring represent the hydroxyl groups formed by the cyclol reactions, whereas the three outer red atoms represent the oxygens of carbonyl groups.  The inner oxygen atoms are separated by only 2.45 Å, which is extremely close even for hydrogen-bonded atoms.  This hypothetical molecule has not been observed in nature.
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