Problem Solved* (*sort of)

at the U.S. National Institutes of Health, saw something that continues to perplex and inspire researchers to this day. Anfinsen was studying an RNA-chewing protein called ribonuclease (RNase). Like all proteins, RNase is made from a long string of building blocks called amino acids that fold up into a particular three-dimensional (3D) shape to give RNase its chemical abilities. Anfinsen raised the temperature of his protein, causing it to unravel into a spaghettilike string. When he cooled it back down again, the protein automatically refolded itself into its normal 3D shape. The implication: Proteins aren’t folded by some external cellular machine. Rather, the subtle chemical push and pull between amino acids tugs proteins into their 3D shapes. But how? Anfinsen’s insights helped earn him a share of the 1972 Nobel Prize in chemistry—and laid the foundation for one of biology’s grand challenges. With an astronomical number of ways those chains of amino acids can potentially fold up, solving that challenge has long seemed beyond hope. But now many experts agree that key questions have been answered. Some even assert that the most daunting part of the problem—predicting the structure of unknown proteins—is now within reach, thanks to the inexorable improvements in computers and computer networks. “What was called the protein-folding problem 20 years ago is solved,” says Peter Wolynes, a chemist and protein-folding expert at the University of California, San Diego. Most researchers won’t go quite that far. David Baker of the University of Washington, Seattle, believes that such notions are “dangerous” and could undermine interest in the f ield. But all agree that long-standing obstacles are beginning to fall. “The f ield has made huge progress,” says Ken Dill, a biophysicist at the University of California, San Francisco (UCSF). The work has huge implications for medicine. Misfolded proteins lie at the heart of numerous diseases, including Alzheimer’s and Creutzfeldt-Jakob disease. Understanding how proteins fold could shed light on why they sometimes misfold and could suggest ways to intervene. Accurate protein models can also lead to the development of more-conventional drugs that block or enhance the work of key proteins in the body.