37  Folding of proteins

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A protein must have a very specific three-dimensional shape in order to correctly exercise its function in a cell. Although only fractions of a second are required for a single protein folding to be completed in a cell, it would take billions of years to run through all of the possibilities for a single folding! Here it is necessary to know that an incorrectly-folded protein usually has a negative effect for the living creature (in the worst case, even death). For the formation of one single cell, it is necessary for thousands of proteins to be correctly folded. This leaves very little leeway for random processes.

The first step in the formation of protein is synthesis of a linear sequence of amino acids (primary structure). However, a protein can accomplish its actual function only when a precisely defined three-dimensional structure is present in addition to the specific sequence. This structure consists of characteristic structural elements (secondary structures), which for their part are folded in a higher-level spatial arrangement (tertiary structure). Moreover, aggregations of a number of proteins are known, which for their part have a specified structure (quaternary structure).

The problem of protein folding:
Proteins control nearly all functions in the human body. The folding determines the function of the proteins. Any change in the protein folding results in a change of function. Even a minute change in the folding process of an otherwise beneficial protein can cause disease.
Since the number of possible protein folding increases exponentially with the length of the amino acid chain, the time required to try all possible foldings (conformations) requires several billion years even for a small protein. In practice, however, a precisely-defined spatial structure is made within fractions of a second.

This phenomenon, known as the Levinthal paradox, clearly indicates that proteins obviously do not run through all possible foldings, but rather find short cuts on the way to their final structure with the aid of the so-called chaperones. The question which arises here is how the so-called chaperones know how the proteins have to look like in their final form. As with the formation of the primary structure, the formation of the tertiary and quaternary structure requires information, which cannot have originated on its own, because the final form must be known in advance. 

Virtual protein folding with Blue Gene:
In 2005, IBM developed Blue Gene, the highest performance supercomputer in the world at that time in order to solve the problem of protein folding (1). The reason for this development is given on IBM’s internet site: “The community of scientists considers the problem of protein folding to be one of the greatest challenges – a fundamental problem for science … whose solution can be achieved only by use of extremely high performance computer technology.”
In spite of the enormous research power used here, it is estimated that Blue Gene would require approximately one year to complete the calculations for a model for folding a simple protein. A researcher at IBM mentioned, “The complexity of the problem and the simplicity with which it is solved in the human body is absolutely astounding” (2).

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(1) IBM, Blue Gene Research Project, 2003, http://www.research.ibm.com/bluegene/index.html.
(2) S. Lohr, IBM plans supercomputer that works at the speed of life, New York Times, 6 December, 1999, C-1.

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