By September 1951, the account of Pauling’s scientific achievement had made it even into the pages of Life magazine, where a photograph of a grinning Pauling pointing to his alpha-helix model was accompanied by the headline “Chemists Solve a Great Mystery: Protein Structure Is Determined.” The Life article was but a brief summary, in lay terms, of what had been a truly miraculous year in Pauling’s long career. Suffice it to note that the May 1951 issue of the Proceedings of the National Academy of Sciences contained no fewer than seven papers by Pauling and his collaborator, chemist Robert Corey, on the topic of the structure of proteins ranging from collagen (the most abundant protein in mammals) to the shafts of feathers. This publication marked the culmination of fifteen years of trailblazing research by Pauling.

Pauling started to think about proteins in the 1930s. His first papers on the subject proposed a theory for hemoglobin—the iron-containing protein in red blood cells—suggesting that each of the four iron atoms in the molecule formed a chemical bond with an oxygen molecule. While working on that subject, Pauling pioneered a new experimental technique. He came up with the idea that measuring the magnetic properties of some proteins could provide important information on the nature of the bonds formed by iron atoms with the groups surrounding them. The method has indeed proved to be a fruitful tool in structural chemistry. Pauling used the magnetic characteristics to good effect; for instance, to determine the rates of several chemical reactions.

Around the same time, Alfred Mirsky, a leading protein expert, came to Pasadena for a year to work with Pauling’s group. This chance collaboration between the two scientists became the starting point for an immensely successful quest. Mirsky and Pauling first proposed that a native protein—that is, an unaltered protein in its natural state inside the cell—is composed of chains of amino acids known as polypeptides, which are folded in some regular fashion. Very soon thereafter, Pauling realized that a key question was the precise nature of this folding. Fortunately, a few clues were starting to emerge in the early 1930s from X-ray diffraction experiments. In this powerful technique, scientists shine an X-ray beam onto a crystal. Then they can attempt to reconstruct the structure of the crystal (in terms of distances between atoms and their mutual orientations) from the way the invisible rays bounce off the sample. Pauling had at his disposal X-ray diffraction patterns obtained by the physicist William Astbury from hair, wool, horns, and fingernails (proteins known as alpha keratin). The X-ray photographs were rather fuzzy, however, and they did not allow for reliable structure determinations. Nevertheless, the photos did appear to indicate that the structural unit was repeating along the hair’s axis every 5.1 angstroms. (One angstrom is a unit of length equal to one hundred-millionth of a centimeter.) Given the relatively poor quality of the X-ray patterns, Pauling decided to attack the problem from the other end: to use structural chemistry—the expected interactions among atoms—to predict the dimensions and shape of the polypeptide chain, and then to check which one of the various potential configurations was consistent with the information deduced from the X-ray images.

Pauling immersed himself in the work on the folding riddle in the early summer of 1937, when he was finally free of his teaching duties. Figure 11 shows a schematic drawing of the type of general structure that he was considering. By scrutinizing carefully the chemical bond between the carbon atom (denoted by “C” in the figure) and its adjacent nitrogen atom (denoted by “N”), Pauling concluded that the carbon, nitrogen, and the four neighboring atoms (collectively known as the peptide group) had to lie in the same plane. This particular feature turned out to be extremely important because it restricted greatly the number of possible structures, and Pauling therefore hoped to be able to pin down the correct configuration. Science, however, rarely proceeds precisely as expected. In spite of several weeks of very intensive work, Pauling was unable to find a way of folding the peptide chains that would reproduce the repeat every 5.1 angstroms along the fiber axis that the X-ray results seemed to indicate. Frustrated, he gave up at that point.