Anfi n sen and his colleagues at the Na tional Institutes of Health made a remarkable discovery. They were explor ing a long-standing puzzle in biology: What causes newly made proteins which resemble loosely coiled strings and are inactive-to wind into specifi cally shaped balls able to perform cru cial tasks in a living cell? In the process the team found the answer was simpler than anyone had imagined. It seemed the amino acid sequence of a protein, a one-dimensional trait, was fully sufficient to specify the mole cule's ultimate three-dimensional shape and biological activity.(Proteins are built from a set of just 20 amino acids, which are assembled into a chain ac cording to directions embedded in the genes.) Outside factors, such as en zymes that might catalyze folding, did not have to be invoked as mandatory participants.

The discovery, which has since been confirmed many times-at least for rel atively small proteins-suggested that the forces most responsible for proper folding in the cell could, in theory, be derived from the basic principles of chemistry and physics. That is, if one knew the amino acid sequence of a protein, all that would have to be con sidered would be the properties of the individual amin o acids and their behav ior in aqueous solution.(The interior of most cells is 70 to 90 percent water.) In actuality, predicting the confor mation of a protein on the basis of its amino acid sequence is far from sim ple. More than 30 years after sen made his breakthrough, hundreds of investigators are still at work on that challenge, which has come to be widely