On the Formation of Antibodies

By the 1940s, Linus Pauling’s research interests had expanded to include many subjects generally outside the purview of a typical chemist. In particular, immunology was rapidly becoming a fascination of his – one that would come to devour more and more of his time both in and out of the lab. For Pauling, much of the human body could be viewed as a gigantic set of very complicated chemistry problems, and he derived great joy from being able to solve some of these problems. Among his most important immunological discoveries were his elucidation of the role that hemoglobin plays in sickle cell anemia and his theory of antibody formation.  The latter is the topic of today’s post.

In 1940 Pauling published a paper – now his ninth most cited – in the Journal of the American Chemical Society on the subject of antibodies and antigens. This manuscript, titled “A Theory of the Structure and Process of Formation of Antibodies” is fundamentally based around one important assumption that Pauling made about antibody structure, “…that all antibody molecules contain the same polypeptide chains as normal globulin, and differ only in the configuration of the chain; that is, in the way that the chain is coiled in the molecule.”

Antibodies are protein molecules that play an extremely important role in the human body. Their main function is to identify and neutralize foreign objects, called antigens, that have been taken up by the body. Antigens come in many varieties, including high-molecular-weight carbohydrates, lipids, pollen and bacterial cells. It is important to note too that only antigens marked by the body’s systems as “foreign” will set off an antibody response; antigens marked as “self” are tolerated by the body.

Pauling with Dan Campbell, a primary colleague in Pauling's antibody work.

Antigens play an important role in Pauling’s theory, which argues that antigens alone determine the configuration of a specific portion of the antibody molecule. For example, without the presence of an antigen, a normal globulin protein will be synthesized. In the presence of an antigen however, a specific antibody will be produced, a portion of which will be complementary in structure to the antigen that in question. In describing this process, Pauling’s paper first details the four steps that occur in the formation of a normal globulin molecule, which are summarized below.

  1. The polypeptide chain is synthesized. The two ends of the chain are free, but the center of the chain is still attached at the site of synthesis.
  2. The ends coil into either their most stable, or another very stable, configuration. Hydrogen bonds and other weak forces between amino acids in the polypeptide chain stabilize the two ends.
  3. The center of the chain is freed from the site of synthesis.
  4. The center coils into its most stable configuration, and the globulin molecule is completed.

Because antibodies are simply modified globulin molecules, the process for their formation is closely related to that of globulin. Summarized below then, are Pauling’s six steps of antibody formation.

  1. An antigen is held in place at the site of antibody production and the antibody is synthesized around the antigen molecule.
  2. The ends of the newly synthesized antibody coil into a configuration complementary to groups on the antigen and attach to these complementary groups.
  3. The center of the chain is freed from the site of synthesis, causing one of two things to happen. If the forces between the ends of the chain are sufficiently strong, both ends will continue to be attached to the antigen, and the antibody will never be completed.
  4. If they forces between the ends of the chain and the antigen are weak, one end will dissociate from the antigen.
  5. Assuming one end of the chain dissociates from the antigen, the center of the chain coils into its most stable configuration, making a complete antibody.
  6. Eventually, the antibody will dissociate from the antigen and float away.

To summarize, Pauling’s theory of antibody formation argues that every antibody has the same configuration in the center of its polypeptide chain, and that the configuration of the ends of the chain are dependent on which antigen is present at the time of the antibody’s synthesis.  In present day, even with our better understanding of antibody synthesis, the core principles of Pauling’s theory – most prominently the idea that each antibody shares a common structure – remain sound.

The entirety of Pauling’s manuscript is available here.  In it, he discusses other topics related to his theory, including the formation of different structures based on antibody to antigen ratios, the characteristics that define a molecule or substance as an antigen, and the compatibility of his theory with experimental results. For more information on Pauling’s immunological work, visit It’s in the Blood: A Documentary History of Linus Pauling, Hemoglobin, and Sickle Cell Anemia.


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