|Early Hemoglobin Investigations
In 1935 Pauling published his first of many scientific papers on the structure of hemoglobin. He approached his research on
hemoglobin by focusing on a portion of the macromolecule. Thus, he first studied the structural configuration of the heme,
which contains the iron. He drew upon his profound knowledge of inorganic chemistry and his growing understanding of organic
substances. Using his knowledge of physics, particularly quantum mechanics, Pauling devised a mathematical explanation to
a problem that stumped researchers: How do the four heme units in the molecule communicate in order to achieve the successive
binding and unbinding of oxygen? It was known that once one oxygen molecule bonded to hemoglobin, that the other three oxygen
molecules bind more readily. The same is true for the unbinding of oxygen molecules: after the first oxygen molecule dissociates
from the hemoglobin, the rest disconnect more easily. Pauling proposed a structure for the four iron atoms in hemoglobin;
he stated that the hemes were not only attached to the globin, but also that the four hemes are arranged in a square and bound
to two other hemes. Thus, Pauling structurally connected the hemes to one another, which explained how they communicate.
Within one year, Pauling, in collaboration with research fellow Charles D. Coryell, wrote two articles on the magnetic properties and structure of hemoglobin and its derivatives. One paper dealt with the
question of how oxygen and carbon monoxide bind to hemoglobin. In order to answer this question, Pauling devised a new approach
for examining hemoglobin – through its magnetic properties. Pauling and Coryell found that oxyhemoglobin and carbonmonoxyhemoglobin
have no magnetic moment and therefore all electrons are paired. In comparison, hemoglobin exhibits paramagnetism, meaning
that hemoglobin has unpaired electrons. Specifically, Pauling and Coryell stated that each heme has four unpaired electrons.
Thus, they determined that the iron in hemoglobin forms ionic (not covalent) bonds with nitrogen and the globin, while oxyhemoglobin
and carbonmonoxyhemoglobin form covalent bonds at the same locations. They remarked: "It is interesting and surprising that
the hemoglobin molecule undergoes such an extreme structural change on the addition of oxygen or carbon monoxide." According
to Pauling and Coryell, the formation of covalent bonds (rather than ionic bonds) most likely explained why hemoglobin bonded
more readily with oxygen and carbon monoxide than with other substances. Pauling reflected in 1970 upon the importance of
his work with Coryell: "These studies of the magnetic properties of hemoglobin and its compounds led to a great increase in
understanding of the structure of the hemoglobin molecule in the neighborhood of the heme groups."
Although Pauling valued hemoglobin's potential, he neither asked others to research it, nor did he make it a primary research
substance in Caltech's chemistry laboratory after he became the department's Chair in 1937. Of the fifteen men who headed
up areas of research in Pauling's lab, only Pauling worked on hemoglobin. And of his seven assistants, only two aided him
with his hemoglobin projects during the late 1930s. However, this did not stop Pauling from importing scientists familiar
with hemoglobin to help him learn more about it.