page_title: Cyclol
section_title: Implausibility of the model
hierarchical_section_title: Cyclol / Implausibility of the model
caption_attribution_description: Space-filling image of an alanine cyclol "fabric" proposed by Dorothy Maud Wrinch in 1936 (Nature, _137_, 411-412), as seen from the side where none of the Cβ atoms emerge. This Figure shows the three-fold symmetry of the fabric and also that its extraordinarily density; for example, in the "lacunae" — where three Cβ atoms (shown in green) and three Hα atoms (shown as white triangles) converge — the carbons and hydrogens are separated by only 1.68 Å. The red atoms represent hydroxyl groups (not carbonyl oxygen atoms). The larger green spheres represent the Cβ atoms; the Cα atoms are generally not visible, except as little triangles next to the blue nitrogen atoms. 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: The cyclol fabric was shown to be implausible for several reasons.  Hans Neurath and Henry Bull showed that the dense packing of side chains in the cyclol fabric was inconsistent with the experimental density observed in protein films. Maurice Huggins calculated that several non-bonded atoms of the cyclol fabric would approach more closely than allowed by their van der Waals radii; for example, the  inner Hα and Cα atoms of the lacunae would be separated by only 1.68 Å (Figure 5).  Haurowitz showed chemically that the outside of proteins could not have a large number of hydroxyl groups, a key prediction of the cyclol model, whereas Meyer and Hohenemser showed that cyclol condensations of amino acids did not exist even in minute quantities as a transition state.   More general chemical arguments against the cyclol model were given by Bergmann and Niemann and by Neuberger.  Infrared spectroscopic data showed that the number of carbonyl groups in a protein did not change upon hydrolysis, and that intact, folded proteins have a full complement of amide carbonyl groups; both observations contradict the cyclol hypothesis that such carbonyls are converted to hydroxyl groups in folded proteins.  Finally, proteins were known to contain proline in significant quantities (typically 5%); since proline lacks the amide hydrogen and its nitrogen already forms three covalent bonds, proline seems incapable of the cyclol reaction and of being incorporated into a cyclol fabric.  An encyclopedic summary of the chemical and structural evidence against the cyclol model was given by Pauling and Niemann.  Moreover, a supporting piece of evidence—the result that all proteins contain an integer multiple of 288 amino-acid residues—was likewise shown to be incorrect in 1939.
  Wrinch replied to the steric-clash, free-energy, chemical and residue-number criticisms of the cyclol model.  On steric clashes, she noted that small deformations of the bond angles and bond lengths would allow these steric clashes to be relieved, or at least reduced to a reasonable level.  She noted that distances between non-bonded groups within a single molecule can be shorter than expected from their van der Waals radii, e.g., the 2.93 Å distance between methyl groups in hexamethylbenzene.  Regarding the free-energy penalty for the cyclol reaction, Wrinch disagreed with Pauling's calculations and stated that too little was known of intramolecular energies to rule out the cyclol model on that basis alone.  In reply to the chemical criticisms, Wrinch suggested that the model compounds and simple bimolecular reactions studied need not pertain to the cyclol model, and that steric hindrance may have prevented the surface hydroxyl groups from reacting.  On the residue-number criticism, Wrinch extended her model to allow for other numbers of residues.  In particular, she produced a "minimal" closed cyclol of only 48 residues, and, on that (incorrect) basis, may have been the first to suggest that the insulin monomer had a molecular weight of roughly 6000 Da.
  Therefore, she maintained that the cyclol model of globular proteins was still potentially viable and even proposed the cyclol fabric as a component of the cytoskeleton.  However, most protein scientists ceased to believe in it and Wrinch turned her scientific attention to mathematical problems in X-ray crystallography, to which she contributed significantly.  One exception was physicist Gladys Anslow, Wrinch's colleague at Smith College, who studied the ultraviolet absorption spectra of proteins and peptides in the 1940s and allowed for the possibility of cyclols in interpreting her results.  As the sequence of insulin began to be determined by Frederick Sanger, Anslow published a three-dimensional cyclol model with sidechains, based on the backbone of Wrinch's  1948 "minimal cyclol" model.
caption: Figure 5: Spacefilling diagram of the alanine cyclol fabric, as seen from the side where none of the Cβ atoms emerge.  This Figure shows the threefold symmetry of the fabric and also its extraordinary density; for example, in the "lacunae"—where three Cβ atoms (shown in green) and three Hα atoms (shown as white triangles) converge—the carbons and hydrogens are separated by only 1.68 Å.  The larger green spheres represent the Cβ atoms; the Cα atoms are generally not visible, except as little triangles next to the blue nitrogen atoms.  As before, the red atoms represent hydroxyl groups, not carbonyl oxygen atoms.
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