13 - Lecture 12: Protein Folding Friday, August 20, 2010 A...

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Lecture 12: Protein Folding Friday, August 20, 2010
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A fundamental question facing modern biochemistry is how does the primary sequence dictate the three- dimensional fold of a protein? This is best stated as the LEVINTHAL PARADOX: A typical protein of 100 amino acids in length, has available to it an ENORMOUS number of potential conformations. Even just considering the backbone phi and psi angles, if a protein randomly searched each possible conformation for the right one (folded), and did so at the rate of 1 conformation each 10 picoseconds (1x10 -13 sec), it would take the protein the lifetime of the universe to Fnd that single folded state! time = 10 N / 10 13 s -1 = 10 87 seconds Yet, common sense tells us that this cannot be true. The typical protein folds in ms to seconds…. How can we resolve this paradox? Friday, August 20, 2010
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In 1957, Christian Anfsen showed that the primary sequence oF RNase A dictates the tertiary Fold oF the protein. The experiment: Friday, August 20, 2010
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The result was that after dialyzing the solution to remove the urea and mercaptoethanol and exposing the solution to oxygen at pH 8.0, the protein spontaneously refolded, with nearly 100% of the proteins having the correct set of disulFdes. If this process was random (disulFde bond formation) the fraction of proteins containing the correct disulFdes would be: 1/7 x 1/5 x 1/3 x 1/1 = 1/105 Clearly, not a random process. Friday, August 20, 2010
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presence of urea, which results in a “scrambled” RNase in which the disulFdes are randomly formed. HOWEVER, adding a trace of mercaptoethanol over the period of 10 hours allows the protein to slowly fold back into the correct state. Friday, August 20, 2010
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This note was uploaded on 11/12/2010 for the course CHEN 3320 at Colorado.

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13 - Lecture 12: Protein Folding Friday, August 20, 2010 A...

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