Thinking Structurally: The Roots of Pauling’s Hemoglobin Work

Pastel drawing of Hemoglobin at 20 angstroms, 1964. Drawing by Roger Hayward.

Pastel drawing of Hemoglobin at 20 angstroms, 1964. Drawing by Roger Hayward.

Linus Pauling is one of that select group of individuals whose lives have made a discernible impact on the contemporary world. His contributions to molecular chemistry have been substantial and fully deserving of the recognition that he received in the form of a Nobel Prize in chemistry….Pauling continued to do productive scientific work throughout his lifetime, making a second outstanding contribution in his discovery of the molecular processes involved in sickle-cell anemia. This discovery, if made by anyone who was not already the only person to receive two unshared Nobel Prizes, might well have merited a third prize in medicine.
– Ted Goertzel. “Linus Pauling: The Scientist as Crusader.” Antioch Review, 38 (1980): 371-382. 1980.

Two of Linus Pauling’s greatest scientific discoveries, his work on the nature of the chemical bond and the discovery of molecular disease, both hinged on his distinctly structural approach to scientific problems.

Having written a doctoral dissertation on the determination of the molecular structure of inorganic compounds in crystalline state, Pauling chose hemoglobin as an object of study in part because he knew that it was hemoglobin’s changing structure that allowed it to carry oxygen to the tissues of the body. While Pauling like to joke that he chose to work on blood because it was easy to obtain, the intellectual challenge of explaining the sigmoid curve of oxygen saturation in hemoglobin profoundly sparked Pauling’s scientific interest.

Later, upon learning about the disease sickle-cell anemia, Pauling came to recognize that the potentially molecular and structural basis of the disease could facilitate a deeper investigation into structural studies of the molecule. Hemoglobin, in part because of its association with the bonding and transport of iron atoms, demonstrated extremely changeable magnetic charges and suggested, even from a preliminary acquaintance, the importance of structural changes in chemical function.

By 1934, when Pauling suggested hemoglobin as the organic molecule of choice for his particular research program, he had already laid out a general plan of research that relied heavily on investigations into the structural and electrically-charged nature of organic molecules. In May of 1935, Pauling wrote in his research notebook

At this time I have analyzed the oxygen equilibrium data to make plausible the idea that in hemoglobin the four hemes are arranged at the corners of a square on one side of the globin, being interconnected along the edges of the square, and that in the hemochromogens the hemes are independent of one another; and I have outlined a general program of investigation, consisting mainly of magnetic studies and x-ray studies (anomalous dispersion, radial distribution about iron atoms).

In a way, Pauling had always been thinking structurally about the nature of the hemoglobin molecule, its ability to bind oxygen molecules and, later, its particular pathology in the case of sickle-cell anemia.

In 1937, Pauling delivered an inaugural lecture for the Sigma Xi society of Corvallis, in which he asserted both the importance and the relatively-recent arrival of structural chemistry as a discipline. For Pauling structural chemistry involved “the determination of the structures of molecules – the exact location of the atoms in space relative to one another – and the interpretation of the chemical and physical properties of substances in terms of the structure of their molecules.”

This lecture, entitled “Hemoglobin and Magnetism,” addressed the “new branch of chemistry, modern structural chemistry” through a discussion of some of Pauling’s most recent work on hemoglobin’s magnetic properties.