Cyclol - Illustration of The Scientific Method

Illustration of The Scientific Method

The cyclol model of protein structure is an example of empirical falsifiability acting as part of the scientific method. An original hypothesis is made that accounts for unexplained experimental observations; the consequences of this hypothesis are worked out, leading to predictions that are tested by experiment. In this case, the key hypothesis was that the cyclol form of the peptide group could be favored over the amide form. This hypothesis led to the predictions of the cyclol-6 molecule and the cyclol fabric, which in turn suggested the model of semi-regular polyhedra for globular proteins. A key testable prediction was that a folded protein's carbonyl groups should be largely converted to hydroxyl groups; however, spectroscopic and chemical experiments showed that this prediction was incorrect. The cyclol model also predicts a high lateral density of amino acids in folded proteins and in films that does not agree with experiment. Hence, the cyclol model could be rejected and the search begun for new hypotheses of protein structure, such as the models of the alpha helix proposed in the 1940s and 1950s.

It is sometimes argued that the cyclol hypothesis should never have been advanced, because of its a priori flaws, e.g., its steric clashes, its inability to accommodate proline, and the high free energy disfavoring the cyclol reaction itself. Although such flaws rendered the cyclol hypothesis implausible, they did not make it impossible. The cyclol model was the first well-defined structure proposed for globular proteins, and too little was then known of intramolecular forces and protein structure to reject it immediately. It neatly explained several general properties of proteins and accounted for then-anomalous experimental observations. Although generally incorrect, some elements of the cyclol theory were eventually verified, such as the cyclol reactions and the role of hydrophobic interactions in protein folding. A useful comparison is the Bohr model of the hydrogen atom, which was considered implausible from its inception, even by its creator, yet led the way to the ultimately correct theory of quantum mechanics. Similarly, Linus Pauling proposed a well-defined model of DNA that was likewise implausible yet thought-provoking to other investigators. The cyclol story is an example of where an area of science progressed by formulating a well-defined hypothesis, testing it and eliminating it as incorrect.

Conversely, the cyclol model is an example of an incorrect scientific theory of great symmetry and beauty, two qualities that can be regarded as signs of "obviously true" scientific theories. For example, the Watson-Crick double helix model of DNA is sometimes said to be "obvious" because of its plausible hydrogen bonding and symmetry; nevertheless, other, less symmetrical structures of DNA are favored under different conditions. Similarly, the beautiful theory of general relativity was considered by Albert Einstein as not needing experimental verification; yet even this theory will require revision for consistency with quantum field theory. The example of the cyclol model illustrates that all scientific theories, even the most beautiful and symmetrical, must be tested by experiment and that no theory is obviously true a priori, only more plausible.