Linus Pauling and the Structure of Proteins: A Documentary History Narrative  
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Mirsky and Pauling
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Using the promise of interesting research, steady money, and California sunshine, Pauling convinced Mirsky to come to Pasadena for two years starting in the summer of 1935. It was the beginning of a fruitful collaboration. Mirsky, too, believed in Fischer's long-chain model of protein structure. Pauling and Mirsky began putting together a picture of how a long chain might conform to a two-step model of denaturation.

The conclusion they came up with, after some months of brainstorming and experimental work, was that proteins did indeed consist of long chains of amino acids, each connected to the next with a covalent peptide bond. That much Fischer had already postulated. But Pauling and Mirsky went farther. Once formed, the chains, they thought, might then be looped or twisted into specific shapes, with weaker hydrogen bonds connecting one part of the chain with another, pinning the final structure into place. Breaking the hydrogen bonds with gentle heating would leave the chain intact but without its native shape, strung out, denatured; careful cooling of the denatured protein would allow the hydrogen bonds to reform and the chain would return to its original shape and activity. That explained reversible denaturation. More severe treatment, however, higher heat or stronger acids, would not only destroy the hydrogen bonds but also would sever some of the covalent links holding the chain together, breaking it into pieces. Once the covalent bonds were broken, cooling would not rejoin them. The denaturation would be irreversible.

They published a paper on the subject in 1936. In a few clear sentences, they summarized what they believed to be a basic structural feature of all proteins: "Our conception of a native protein molecule (showing specific properties) is the following. The molecule consists of one polypeptide chain which continues without interruption throughout the molecule," they wrote. "This chain is folded into a uniquely defined configuration, in which it is held by hydrogen bonds." The work cleverly explained two-step denaturation, and it did more. Pauling and Mirsky were proposing that all proteins were basically the same at one level – they were all long chains of amino acids – but differed in their properties because of their final shape. In their view it was this specific shape, delicately held in place by weak bonds, that gave each protein its personality. Shape was everything.

Their paper, published in the Proceedings of the National Academy of Sciences, was quickly recognized as an important advance in protein studies. It appeared that Warren Weaver's belief in Pauling was paying off.

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Audio Clip  Audio: Close Contact with Alfred Mirsky. October 14, 1992. (1:08) Transcript and More Information

Video Clip  Video: Folding Polypeptide Chains. 1960. (0:56) Transcript and More Information

See Also: Letter from Linus Pauling to Alfred E. Mirsky. May 25, 1937. 
See Also: Letter from Alfred E. Mirsky to Linus Pauling. January 6, 1938. 

Click images to enlarge 

Page 32
Pauling Diary: "Addresses." 1935.

Page 439
"On the structure of native, denatured, and coagulated proteins." July 1936.

"In suggesting that hydrogen bonds determined the three-dimensional configuration of proteins - and thus their biological specificity - Pauling and Mirsky enunciated a fundamental relation between molecular structure and biological function. It was also one of the cornerstones of Pauling's conception of molecular architecture, a metaphor and method for explaining life in health and disease, which would lend legitimacy to the molecular biology enterprise."

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