Web Bit 3-3: Linus Pauling and the Alpha Helix
By Jennie Dusheck

One day in April of 1948, the American physical chemist Linus Pauling lay in a bed near Oxford University, in England, patiently weathering a nasty cold. As he sniffled, he drew chemical diagrams on a sheet of paper. He picked up the sheet of paper and folded a few creases into it, curling and bending the paper this way and that. Then he tried refolding the creases so that they bent at different angles. Suddenly, he had it.

Figure 3.3a: Linus Pauling (1901–1994). Pauling made major contributions to chemistry, which he summarized in his influential book, The Natue of the Cmenical Bond. He was largely responsible for the concept of electronegativity, and he won two Nobel Prizes: one for his scientific work, and one for his efforts on behalf of world peace, which led to the 1964 treaty outlawing atmospheric tests of nuclear weapons.

For 11 years Pauling had worked off and on trying to find a general structure for proteins, and now he was almost certain he knew the answer (Figure 3.3a). He was not certain enough to tell anyone, but he was certain enough to return to his laboratory at Caltech, in Pasadena, California, and perfect the idea. It would be more than two and a half years before he made his revolutionary discovery public.

The story behind Pauling's discovery began at the beginning of the 20th century, when the German physicist Max von Laue invented a technique for studying the internal structure of crystals. Crystals are solids whose regular geometric shapes reflect the regular arrangement of their atoms. Ice, sugar, salt, and glass, for example, all form crystals. When light passes through a crystal, the light bends and spreads out into a rainbow. This is the same effect that produces the rainbow of colors in a polished diamond.

X rays also bend as they pass through crystals. In 1912, von Laue was able to show that a crystal can scatter—or diffract—x rays in such a way that they form a pattern of spots that can be recorded on photographic film. Von Laue found that the pattern of spots reflected the arrangement of the atoms and molecules inside the crystal. His new technique, called x-ray crystallography—or x-ray diffraction—consisted of analyzing the scattering or "diffraction" of x rays by crystals.

Soon after von Laue's discovery, two British physicists, William Henry Bragg and his son Lawrence Bragg, showed that analysis of x-ray diffraction patterns could reveal the precise atomic structure of the molecules in a crystal. Because each atom in a crystal contributes to the pattern of spots, crystallographers can calculate the structure of the individual molecules of the crystal from the intensities of these spots. The Braggs' discovery allowed the determination of all the molecular structures that we will discuss in the rest of this chapter.

In 1927, young Linus Pauling went to visit the Braggs' laboratory in England and came away with enough of an understanding of their new technique to use it himself. He formalized a set of six rules describing how relations among atoms determine their position in a molecule. For example, he described how sizes and electrical charges of atoms determine their arrangement in a molecule. Pauling's rules influenced generations of chemists.

In 1934, the English chemist J. D. Bernal showed that not only small molecules could be studied with x-ray crystallography, but also proteins and other giant molecules. Bernal's 1934 discovery opened the door to the possibility of untangling the structures of proteins. Proteins were known to be composed of smaller units called amino acids. But no one knew how the amino acids were arranged within the protein. Some scientists envisioned proteins as long chains of amino acids. Others thought they were more like cages of linked amino acid rings.

In 1937, Pauling devised a spiraling chain of amino acids that conformed to his notion of what a protein molecule might look like. However, his model conflicted with results from x-ray crystallography studies. To try to come up with a better model, Pauling and his colleague Robert Corey began a 12-year study of the structures of the individual amino acids. By 1948, the two men knew more about the structures of amino acids than anyone else in the world, and they could accurately predict what kinds of bonds each amino acid would form with any other—including the exact lengths and angles of each of those bonds. Pauling had every reason to be confident that he and Corey would eventually determine the structure of protein.

So when, in 1948, Pauling found himself bored and sick in bed at Oxford, he couldn't help thinking about the problem. With his now incomparable knowledge of the chemistry of amino acids, he soon realized that the dimensions of the spiraling chain he had conceived in 1937 were, in fact, probably correct. (Research published in 1950 showed what Pauling had long suspected: The x-ray crystallography study that had conflicted with his original ideas about proteins had been wrong. The photos were accurate enough, but the researcher had misunderstood what they meant.) In 1948, Pauling could see that if he adjusted the steepness of the spiral just so, hydrogen bonds connected the turns, holding the spiral in place.

Meanwhile, Lawrence Bragg and several other researchers at Cambridge University had also become fascinated by the structure of proteins. They threw themselves at the problem, and, in the spring of 1950, published a scientific paper that suggested that the amino acids in a protein called alpha keratin were arranged in a ribbonlike chain that folded back and forth, like a chain of paper dolls. It was an article that, for the rest of their lives, they would regret publishing.

Back at Caltech, Pauling and Corey had begun building large and detailed models of various proteins—including keratin, the protein found in hair, hooves, and horn. The two scientists adhered strictly to the rules that they had learned over the years, confirming that Pauling's spiral model was possible and likely. In the fall of 1950, the two scientists announced their discovery in a short letter to a respected journal of chemistry.

Soon afterward, Pauling gave a memorable lecture describing the results of the 15 years of work. Scientists jammed into the lecture hall to find out what Pauling had discovered, and the charismatic chemist entertained his audience with pointed references to the Cambridge group's mistake. Bragg and his colleagues had failed because, as Pauling later put it, they were ignorant of the "principles of chemistry, of structural chemistry."

The following spring, Pauling and Corey published a long series of papers describing the structures of several important proteins, including the blood protein hemoglobin and various proteins found in hair, feathers, muscle, silk, and gelatin. They described in detail several structural forms, including the spiral amino acid chain envisioned by the bedridden Pauling. Pauling called the spiral structure an a (alpha) helix (Figure 3.3b). The biochemical community was bedazzled.

Figure 3.3b: The a helix, as envisioned by Linus Pauling. Hydrogen bonds connect one loop to the next, holding the structure in a stable configuration.

Bragg was furious, mainly with himself. In his rush to publish something about the structure of proteins, he had gone completely astray. His colleague Max Perutz, whose name was also on the notorious Cambridge paper, was so beside himself that he immediately thought of a way to test Pauling's idea. If keratin really had an a helix structure, Perutz reasoned, then x-ray crystallography should show a spot where no one had ever reported one before.

Perutz knew that there were only two possible reasons that no one had seen the spot. Either the spot didn't exist, and Pauling and Corey were wrong, or else no one had set up a keratin molecule at the right angle. It was a Saturday, but only an hour or two after he had finished reading Pauling and Corey's series of papers, he went to his lab. He found a horsehair—a rich source of keratin—set the hair at the angle he had calculated was necessary to show the spot, then took a single x-ray diffraction photo. There was the spot.

Perutz's spot was the first independent experimental confirmation of Pauling's hypothesis. Perutz later showed that the a helix could be found in a variety of proteins, just as Pauling had predicted. In 1954, Pauling received a Nobel prize for his work with Corey on the structures of large molecules. Eight years later, in 1962, Perutz also received a Nobel prize for his contributions.

Pauling and Corey's work was some of the finest work on the structure of large molecules that has ever been done. In this chapter we will explore a few of the chemical principles that determine how biological molecules, both small and large, fit together. Many of these are the same principles that made Pauling's work possible.

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