A Theory of the Denaturation of Proteins

Alfred E. Mirsky, 1960s

In 1935, as a result of being prompted toward the biological sciences in order to keep his Rockefeller Foundation funding, Linus Pauling began his research on proteins. Hemoglobin, the oxygen-binding agent in blood, was his first target; but as he became more aware of the complex nature and diversity of proteins, he began contemplating broader topics related to the subject – one of which was the theory of protein denaturation.

In the spring of 1935, Pauling traveled to the Rockefeller Institute in New York City, where he met Dr. Alfred Mirsky. Mirsky was a Rockefeller scientist who had previously conducted denaturation research, and because of his new interest in the subject, Pauling arranged for Mirsky to spend fifteen months working with him at Caltech. Although initially hesitant, Mirsky eventually agreed, and the pair began collaborating in the summer of 1935.

In July 1936, the duo’s paper, titled “On the Structure of Native, Denatured, and Coagulated Proteins” was published in the Proceedings of the National Academy of Sciences.  In this paper, the authors loosely describe protein denaturation as “the loss of certain highly specific properties by the native protein,” and provide examples of the types of changes that have been experimentally observed.

In so doing, Pauling and Mirsky point out that while many proteins in their native form have been crystallized, no denatured protein exist in this state. Likewise, in proteins that act as enzymes, denaturation causes a disappearance of the enzymatic activity.  And one fact that was of particular interest to Pauling was that the process of denaturation is occasionally reversible.

Early Pauling notes on the characteristics of protein denaturation, ca. 1935

As researchers are now aware, any given protein has a certain structure – or rather, four different structural levels – that needs to be maintained in order for the molecule to function correctly. Although this crucial bit of information was still unknown at the time of Pauling and Mirsky’s research, the authors essentially touch on this exact detail in their 1936 paper:

Our conception of a native protein molecule (showing specific properties) is the following. The molecule consists of one polypeptide chain [the amino acid sequence] which continues without interruption throughout the molecule (or in certain cases, of two or more such chains); this chain is folded into a uniquely defined configuration, in which it is held by hydrogen bonds…

The collaborators further posited that, as a result of this “structure equals function” characteristic of proteins, denaturation is “characterized by the absence of a uniquely defined configuration” and can be accomplished in a number of different ways, including heating, subjection to ultraviolet light, or an attack by certain reagents.

In presenting their theory of denaturation, Pauling and Mirsky associated both the heating of the protein and its treatment with certain reagents, as leading to the disruption or complete rupturing of hydrogen bonds.  From there they pointed out that ultraviolet light is not able to break a sufficient quantity of hydrogen bonds, and therefore must affect the molecule differently – an impact which they predicted to be an attack on the main polypeptide chain. Consequently, they suggested that denaturation caused by ultraviolet light was irreversible, while methods that disrupt the more easily re-formed hydrogen bonds would be reversible.

Although Pauling and Mirsky weren’t correct in every aspect of their denaturation theory (ultraviolet light does not disturb the polypeptide chain, and denaturation involves more than just the disruption of hydrogen bonds), it provided a strong start for further work.  The Pauling-Mirsky theory also touched on many details of the structure of proteins in their native forms, a field of inquiry that would not be completely elucidated for many years to come.

For more information on Linus Pauling, please visit the Linus Pauling Online portal. For more information on Alfred Mirsky, visit his key participants page within the It’s in the Blood! A Documentary History of Linus Pauling, Hemoglobin, and Sickle Cell Anemia site.

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  1. [...] 1935, Pauling Blog: A Theory of the Denaturation of Proteins [...]

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