Bartusiak, Marcia F., Burke, Barbara, Chaikin, Andrew, Greenwood, Addison, Heppenheimer, T.A., Hoffman, Michelle, Holzman, David, Maggio, Elizabeth J., Moffat, Anne Simon. "10 Fold, Spindle, and Regulate: How Proteins Work." A Positron Named Priscilla: Scientific Discovery at the Frontier. Washington, DC: The National Academies Press, 1994.
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A Positron Named Priscilla: Scientific Discovery at the Frontier
of DNA and the transcription of RNA from DNA. For this work, Anfinsen received the Nobel prize.
Theoretically, then, it should be possible to predict a protein's structure from its amino acid sequence. In fact, to researchers who study protein folding, this is the holy grail, and hundreds are currently attempting to discover the rules that would make this possible. But so far, such efforts have proven frustrating, to put it mildly. This is not surprising.
For a protein composed of just 100 amino acids, a rather small protein, there may be as many as a google (10100) alternative structures that the protein could form, more structures than the number of atoms in the universe, Alber explained. It is amazing, he said, that the protein itself finds the right confirmation, "spontaneously, in a few milliseconds," even though a random search through all possible structures "would take longer than the age of the universe."
To understand how a protein folds, it is necessary to know that protein's three-dimensional structure. Until recently, piecing structure together was such a difficult process—impossible in some cases, taking years in others—that this goal was a dream. Now new developments in protein imaging technologies, x-ray crystallography, and nuclear magnetic resonance (NMR) have enabled researchers to piece structures together within a year, where formerly it could take longer than a decade. Recombinant DNA techniques have made it possible to perform experiments that are beginning to yield some rules of protein folding. And with this information coming in, the dream of predicting three-dimensional structure from amino acid sequence is becoming a tantalizing possibility on the distant horizon of the field.
X-ray crystallography is an ancient technology by scientific standards, dating back to the first half of the century. Rosalind Franklin's crystallographic work was vital to cracking the structure of DNA, and many observers believe that for this contribution she should have shared the Nobel prize with James Watson and Francis Crick. This alleged slight may have had to do with prevailing attitudes about gender.
Crystallography is often the only way to figure out the molecular structure of a protein. The reason is simple. At best, crystallography provides a picture of the entire protein. It accomplishes this by revealing the location of electron densities throughout the protein. These correspond to chemical groups on amino acids.
Nonetheless, the technique frequently does not succeed so marvelously. There are built-in errors of about 5 percent. Furthermore, usually parts of the protein crystallize poorly or not at all, so that the corresponding electron densities leave no signature in the diffraction pattern.