The Alpha Helix

Space-filling model of the alpha helix.

[The Paulings in England: Part 5 of 5]

It has been said that sometimes blessings come in disguise, and so it may be that we have the damp English spring to thank for the elucidation of the alpha-helix structure of alpha-keratin – a fundamental and ubiquitous secondary structure pattern found in many proteins.

Linus Pauling was plagued by sinusitis for much of his time in England, and for three days in March 1948 it had become severe enough to put him in bed (as he was fond of saying over the years, this was before his vitamin C days). After a day spent devouring mystery novels, Pauling asked Ava Helen if she would bring him some paper and his slide rule, at which point he started trying to figure out how polypeptide chains might fold up into a satisfactory protein structure.

Pauling’s canvas was just an ordinary 8 1/2 by 11 inch sheet of paper. His first step was to draw the correct bond angles and distances onto the sheet, as determined from previous x-ray crystallographic work on polypeptides. Next he folded the sheet along parallel lines into a sort of squared-off tube. Doing so allowed him to add in representations of hydrogen bonds, which the impromptu model suggested would form between amino acid residues and, as a result, hold the turns of the polypeptide together.

The model made sense and pretty quickly it was clear that Pauling had discovered something important.  As he later wrote, his folded creation “turned out to be the structure of hair and horn and fingernail, and also present in myoglobin and hemoglobin and other globular proteins, a structure called the alpha-helix .”

Reconstruction of the alpha-helix paper model. Drawn and folded by Linus Pauling, 1982.

Pauling kept this idea to himself until his return to the United States because something didn’t match up quite right with the current laboratory data. Specifically, the turns of Pauling’s helix didn’t mirror the 5.1 angstrom repeat found in all of William T. Astbury‘s x-ray patterns. Pauling’s structure came close, but made a turn every 5.4 angstroms, or every 3.7 amino acid residues.

After his return home, with the assistance of colleagues Robert Corey and Herman Branson, Pauling continued refining his alpha helix structure and developing others, including the beta sheet. Simultaneously, the Caltech group’s chief British rivals at the Cavendish Laboratory published a paper titled “Polypeptide Chain Configurations in Crystalline Proteins.” The paper promised more than it delivered though, and while it listed many possible structures, Pauling found none of them to be likely. The competition was still on.

Pauling was finally convinced to publish when he received word that a British chemical firm called Courtaulds had created a synthetic polypeptide chain that showed no sign of Astbury’s 5.1 angstrom reflection in x-ray diffraction images. This was enough evidence for Pauling to decide that the 5.1 angstrom repeat was, perhaps, not a vital component of all polypeptide chains.  And so it was that in April 1951 Pauling, Corey and Branson published “The structure of proteins: Two hydrogen-bonded helical configurations of the polypeptide chain,” in the Proceedings of the National Academy of Sciences.

After devouring the Pauling group’s results shortly after their publication, Max Perutz headed to the Cavendish lab at Cambridge to check the data himself. Having confirmed the structure in images of horsehair, porcupine quill, synthetic polypeptides, hemoglobin and, for good measure, some old protein films that had been tucked away, Perutz wrote to Pauling, “The fulfillment of this prediction and, finally, the discovery of this reflection in hemoglobin has been the most thrilling discovery of my life.” He then published an analysis of his own data, concluding, “The spacing at which this reflexion appears excludes all models except the 3.7 residue helix of Pauling, Corey and Branson, with which it is in complete accord.”

Video Link: Pauling Recounts His Discovery of the Alpha Helix

It wasn’t until a year later that the mystery of Astbury’s 5.1 angstrom reflection was finally solved. In 1952, on a visit to the Cavendish, Pauling met Francis Crick, the then-graduate student who would go on to play a huge part in the discovery of the structure of DNA. The two maintained similar interests and during a taxi ride around Cambridge found themselves discussing the matter of the alpha helix. “Have you thought about the possibility,” Crick asked Pauling, “that alpha helixes are coiled around one another?” Whether Pauling had or had not considered this possibility remains a point of contention, but Pauling remembered replying that he had, because he had been considering a number of higher-level schemes for his helixes, including some which wound around each other.

Regardless, Pauling returned to Caltech and both he and Crick set to work on the problem. With help from Corey, Pauling discovered a means by which the alpha helixes could wrap around each other in a coiled-coil to produce the problematic 5.1 angstrom found in Astbury’s pictures of natural keratin.  Crick, in the meantime, was conducting a very similar study.  Pauling and Crick, independent of one another, ultimately submitted the solution to this puzzle for publication within days of each other, and at first there was a bit of grumbling as to whom the credit should be awarded. Though Crick’s note was published first, the Cavendish camp eventually conceded that Pauling’s paper included considerably more detail of consequence, and it was finally settled that both scientists had independently come to the same general conclusion.

Pauling receiving his honorary degree from the University of Paris, 1948.

After Pauling’s two fruitful terms as Eastman Professor at Oxford were up in July, the family split their remaining time between travels in Amsterdam, Switzerland and Paris. Pauling rounded off the trip by receiving yet another honorary degree from the University of Paris, and on August 25, 1948, the Paulings set sail once more on the Queen Mary.

His eight months in Europe had been productive and enlightening, but Pauling was ready to return to Pasadena where he could share the myriad ideas he had generated and gathered during his time away from Caltech. As we have seen, he was especially eager to get back to work on proteins, writing shortly before his departure that “I have continued to work on my theory of metals, and have been doing nothing about proteins. However, I am looking forward to being back home, and to thinking about that subject again.”

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One Response

  1. [...] given his great successes in protein research from 1936-1951 and culminating in his elucidation of the alpha-helix.  The question then, is why did he fail to discover the double helix?  Why did he lose the [...]

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