determine the shapes of proteins. We're starting to understand some of the principles that govern shape.''

ANATOMY OF PROTEINS

To illustrate the magnitude of the challenge, Alber projected a diagram of the cellular catalyst ATCase, a large protein consisting of roughly 30,000 atoms. Like many proteins, its convoluted topology is roughly as complex as a tangle of telephone wire, yet it has the structural grace of a suspension bridge or a bicycle wheel.

The structure of proteins is maintained by chemical bonds that form within proteins. Sometimes these are covalent bonds, the powerful forces that bind atoms together to form molecules, but more often they are the much weaker forces such as electrostatic charges that cause some atoms or molecules to associate with one another in solution. Then there are the water-hating side chains that also attract one another and—surprise—repel water. These are also referred to by scientists as "hydrophobic" or just plain "greasy." The difference between covalent bonds and the other forces is analogous to the difference between the strength of the ties of family and friendship.

Both the covalent bonds and the various weaker forces are properties of the building blocks of proteins, small molecules called amino acids. Proteins are chains of amino acids, which are strung together sort of like poppet beads. But instead of uniform inert beads, there are 20 different kinds of amino acids that occur naturally as well as some synthetic ones. The various forces within proteins are properties of the side chains of amino acids.

It is possible to melt the structure of ATCase by adding urea to the solution containing the protein. Melting overcomes the forces between the chemical groups, destroying ATCase's structure, so that the protein chain now flops around like boiling spaghetti. But remove the urea and the chemical groups pull the protein back into its proper shape.

THE SEARCH FOR STRUCTURE: X-RAY CRYSTALLOGRAPHY AND NUCLEAR MAGNETIC RESONANCE

Christian B. Anfinsen was the first to try this experiment, on the enzyme ribonuclease, in the late 1950s. That the protein regained its shape and its natural enzymatic activity in minutes suggested that all the information that directs folding is contained in the amino acid sequence and not in templates, such as the DNA template that directs the replication



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