This paradox is called the Levinthal paradox, after Cyrus Levinthal. Assuming that it would take 10 -13 s to change each conformation, the time required to "test" all conformations would be 5 x 10 34 s or 10 27 years, longer than the age of the universe (14 x 10 9 yr). If each amino acid can adopt only 3 possible conformations, the total number of conformations could be 3 100 = 5 x 10 47. Consider this greatly simplified view of protein folding for a protein containing 100 amino acids.
In either case, given the number of possibly nonnative states, it is amazing that proteins fold to the native state at all, let alone in a reasonable time frame. Folding in vivo is often assisted by other proteins called folding chaperones. It also occurs when a fully-folded protein misfolds (such as during fevers in disease states) and has been prevented from folding by association with other molecules. Folding in vivo occurs as a protein is being made on a ribosome. In vitro folding is done in very defined conditions, typically using low concentrations of small proteins to minimize misfolding opportunities. We will discuss protein folding done in the lab (in vitro) as well as protein folding in the cell (in vivo). Creative Commons Attribution 4.0 International License. \): Protein Folding and Misfolding Landscape Eric H.-L.
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