Linus Pauling and the Structure of Proteins: A Documentary History Narrative  
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Biological Specificity
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The death of the artificial antibody project allowed Pauling to focus on more productive areas of research. In 1943 he and his assistants started putting together a more detailed picture of how, exactly, antibodies were able to stick to antigens. The results of this careful, valuable research would shape Pauling's attitudes toward protein structure for years to come.

By using carefully prepared synthetic antigens along with improved assaying techniques, Pauling was able to show by the War's end that antibodies stuck to antigens not because of typical chemical bonds (covalent or ionic) but because of shape. Antibody and antigen came together like hand and precisely fitted glove, bringing significant areas of their surfaces into very close contact. Their shapes were complementary. That close contact brought into play a set of weak interactions called van der Waal's forces. These were very weak bonds – only a fraction of the strength of a covalent chemical bond – and were nonspecific, operating between almost any two atoms in close contact. However, when the fit between antibody and antigen was just right, the sum of van der Waal's interactions over many atoms (along with occasional hydrogen bonding and the attraction of oppositely charged polar groups) was enough to bind the two together. The key was harnessing many weak forces spread over a relatively large surface area.

But the fit had to be precise. If the complementary shaping of antibody to antigen was off by just an atom or two, Pauling's group found, the binding force declined significantly.

The ability of one molecule in the body to recognize another, and the creation of specific interactions between them – the way an enzyme binds to only one substrate, for instance, or an antibody to a specific antigen – was a central mystery in the new field of molecular biology. Pauling's immunological work after 1943 cast much-needed light on that mystery. The idea of complementary shapes came to dominate Pauling's thinking about protein interactions in the body.

But he was still a long way from understanding with any degree of detail how any individual protein might be built.

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Audio Clip  Audio: Biological Specificity. January 17, 1983. (1:55) Transcript and More Information

Audio Clip  Audio: Pauling's Major Contribution to Enzyme Studies, November 3, 1991. (1:16) Transcript and More Information

Video Clip  Video: The Importance of Weak Forces. February 28, 1995. (0:42) Transcript and More Information

See Also: Letter from Linus Pauling to J.D. Ratcliff. July 24, 1943. 
See Also: "Hapten Inhibition for Heterogeneous Antiserum." August 5, 1943. 
See Also: Letter from Linus Pauling to J. D. Newburgh. February 24, 1944. 
See Also: Letter from Linus Pauling to H. Tarver. April 3, 1944. 
See Also: Letter from Linus Pauling to J. D. Newburgh. May 26, 1944. 
See Also: Letter from Linus Pauling to Frank H. Johnson. June 20, 1944. 

Click images to enlarge 

Page 1
"Molecular Structure and Biological Specificity." July 17, 1947.

Illustration of the process of antibody formation. July 12 - 17, 1948.

"...[T]he complexity of the protein molecule appears to furnish, when viewed in terms of atomic forces, a sufficiently intricate, detailed pattern to make understandable the precise specificity of protein reaction."

Warren Weaver
August 28, 1939
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