Bringing An Enzyme Back To Life

By the 1950s, scientists realized that DNA held the code that allowed

proteins to be synthesized. Nevertheless, how a chain of amino

acids folds into a fully functional protein, with the proper threedimensional

structure, remained a mystery. A mechanism must exist

to assure the proper folding of the protein. But where did that

information come from? In 1957, Christian Anfinsen published the first

evidence that the information for proper folding was held within the

protein itself.

Background

Proteins are made from combinations of 20 amino acids that

then fold into complex structures. The unfolded amino acid

chain is called the primary structure. To have biological activity,

the protein must fold into proper secondary and tertiary

structures. These structures are held together by chemical

interactions between the side chains of the amino acids,

including hydrogen bonds, hydrophobic interactions, and,

at times, covalent bonds. How these higher structures form

has long been a mystery. Does the protein fold correctly as

it is synthesized or does it require the action of other proteins

to correctly fold it? Can it correctly fold on its own

spontaneously?

In the 1950s, Anfinsen was a biochemist interested in

the proper folding of proteins. Specifically, he was investigating

the formation of disulfide bridges, which are covalent

bonds between cysteine side chains that serve as one of

the major anchors holding together the structure of secreted

proteins. He believed that the protein itself contained all the

information necessary for proper protein folding. He proposed

the “thermodynamic hypothesis,” which stated that

the biologically active structure of a protein was also the

most thermodynamically stable under in vivo conditions. In

other words, if the intracellular conditions could be mimi

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