AlphaFold, we also need to look at why the huge challenge of protein folding is so important in the historical context.
It is estimated that everyone remembers the " central law " that they were exposed to in middle school.
The so-called "central law of molecular biology" was first put forward in 1957 by the biologist and Francis Crick, who was a British physicist, in a conference speech. In that speech, Crick made an unforgettable description "DNA→ RNA →protein", where the arrow represents "information flow".
Crick later won the Nobel Prize together with Jim Watson (as well as Morris Wilkins and the unfortunate death of Rosalind Franklin for their significant contributions) because they Published an article in 1953 to solve the double helix structure of DNA-and reveal the explanation on how to accurately copy the genetic information encoded by the base pair sequence in the double helix.
Equally important is that Crick’s extraordinary insight into the basic molecular information flow of life correctly puts forward in a broad sense: how to make the one-dimensional linear sequence of base in DNA (constitute the genetic code) through The corresponding one-dimensional messenger RNA sequence is translated into a one-dimensional sequence of amino acid structural units constituting the polypeptide chain of a protein.
However, despite its greatness, the Central Law does not explain how linear amino acid chains fold into the correct structure of the proteins that make up the 3D molecular machinery of life.
Twelve years later, in another important conference speech delivered in 1969, the American molecular biologist Cyrus Levinthal estimated thatA representative polypeptide chain may theoretically adopt an astonishing 10,300 configurations-which means that it takes longer than the age of the known universe to fold correctly. This is in stark contrast to the observed ability of the protein to achieve its correct 3D shape in just a few seconds. This problem is called the "Leventhal Paradox" of protein folding.
Three years later, in 1972, the American biochemist Christian Afinson won the Nobel Prize for his "thermodynamic hypothesis" based on his research on the protein called ribonuclease, and "In particular, the relationship between the amino acid sequence and the biologically active substance conformation." At the end of his Nobel Prize speech paper, Affinson looked forward to the future. He believed that by then, people can predict how the 3D shape of a protein structure is related to its corresponding genetic code and amino acid sequence. Although
has made preliminary progress, in 1994, due to the limited ability to correctly predict the 3D conformation of the protein from the constituent amino acid sequences, this prompted a group of structural biologists to launch the " protein structure prediction (CASP) competition". What’s especially interesting is that the organizers don’t like the word "match" and prefer "experiment", but in the eyes of outsiders, this is indeed a competition!
This biennial event aims to accelerate research progress in this field. Then every two years, about 100 research teams try to explore how accurately their calculation methods can predict the 3D structure of the protein, and determine the structure through painstaking experience (usually by X-ray crystallography or cryo- electron microscope) ).
Because participants in the Protein Structure Prediction Competition (CASP) are required to "blindly" predict the structure of one hundred proteins, it can be said that CASP challenges each team's ability to make accurate estimates.
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