|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.