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25 March 2016

Anfinsen and the Architecture of Proteins

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If each of the proteins that make up living beings were an origami figure, the instructions for folding them in three dimensions would have to be sought in their amino-acid sequence. The first test of this scientific principle, which is now found in all biology textbooks, was provided in 1961 by an American biochemist named Christian B. Anfinsen (1916-1995), a descendant of Norwegian immigrants, who worked at the United States National Institutes of Health and years later would be awarded a Nobel Prize.

Anfinsen wanted to understand what the spatial organization, or 3D shape, of a protein depended on, essential for its correct functioning. Searching in his experiments for a single molecule whose activity was easily measurable, he opted for ribonuclease, an enzyme that breaks RNA into fragments. And to study it, he had an idea that no one had thought of before: unfold the protein and then test different ways to refold it.

Unfolding a protein involves breaking the molecular bonds, thereby causing the loss of the natural structure of the protein (denaturation) and its biological properties. Anfinsen accomplished this by mixing mercaptoethanol and urea, and the protein changed from being a complex three-dimensional figure to a long stretched chain. The question was whether it would be a reversible change, and if so, would it refold itself exactly the same?

Christian B. Anfinsen demonstrating protein folding. Credit: Richard T. Nowitz

The American biochemist soon answered the question. When the optimum environmental conditions were restored, then voila!, the protein returned to its original shape and recovered 100% of its activity. It was impossible that it was by random chance that it always formed the exact same four original links when refolding itself. Without doubt, some unique instructions existed on how to fold it, and they had to be contained within the protein’s own sequence. The primary structure, he concluded, is all that a protein needs for its correct folding. He had guessed correctly, this mature scientist who was mistaken as a teenager when he believed that all his schoolmates were geniuses except him. Anfinsen had much to contribute to molecular biology and genetics.

In fact, he did not stop there in his research on ribonuclease. Fulfilling Einstein’s maxim that “the important thing is not to stop questioning,” he decided to find out why it was that, among the 104 possible options for folding this enzyme, nature opts for one and not any other. He concluded that it was, essentially, a matter of energy savings. In other words, among all possible configurations, all proteins will opt for the one that consumes the least energy within the cell. This is known as Anfinsen’s dogma, which earned him the Nobel Prize in Chemistry in 1972. It later came to be understood that there exist exceptions to this dogma, called prions, which cause the so-called “mad cow disease” (bovine spongiform encephalopathy), which become infectious precisely because of changes in their three dimensional structure.

3D structure of ribonuclease molecule researched by Anfinsen. Credit: Crédito: Vossman / UCSF Chimera

For the rest of his career, this biochemist and music aficionado —he played the viola and piano for relaxation—mainly devoted himself to developing chromatographic sequencing techniques that permitted the reading of the “code” of many proteins, as well as understanding the workings of some unique living beings, hyperthermophilic bacteria, which live at extremely high temperatures, near the boiling point, a seemingly unimaginable place for the presence of life.

After living through the horrors of World War II during a stay in Denmark, he became an advocate for nuclear disarmament and human rights. During the Cold War, he defended the scientific collaboration between the US and the Soviet Union. Anfinsen was one of the Nobel laureates who expressed his opposition in 1973 to US President Richard Nixon’s decision to give priority to research on cancer. Later, he publicly opposed the science policy of Reagan, who applied harsh cuts to biomedical research. And he was also involved in a rescue mission to Argentina in 1981, to release twelve scientists detained by the military government of dictator Jorge Rafael Videla.

In addition to his political activism, he contributed interesting reflections on the relationship between science and religion. In an exchange of correspondence with physicist Henry Margenau, Anfinsen clarified that although for him the origin of the universe was explained by the Big Bang, and the origin of life was “an inevitable consequence of the evolution of the universe,” he did not consider this incompatible with having religious beliefs. “Religion seeks mystical answers and science responds to human curiosity by means of physical laws that govern the world,” he argued. Regarding his thoughts about the existence of God, he said, “I think only an idiot can be an atheist. We must admit that there is a power or incomprehensible force with unlimited knowledge that launched the universe in the first place. […] It seems obvious that no one will ever understand what actually happens and that the best we can do is to relax and enjoy ourselves.”

Elena Sanz for Ventana al Conocimiento

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