Levinthal's Paradox

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Peter Foster, In progress Fall 2011

Entry needed.


It is well known that proteins in solution can reliably fold from a random coil to a unique native conformation on a biologically relavent timescale. Levinthal's paradox is an apparent contradiction between the number of possible conformations for a protein chain and the fact that proteins can fold to their native conformation quickly (less than a second). In the proceedings where Levinthal first mentioned the paradox that bears his name (Reference 1), he estimates that for a protein there are 10300 possible conformations. Using the amount of time it actually takes for a protein to fold to its native conformation and assuming the minimal amount of time to sample different conformations, the protein would only be able to sample ~108 different conformations if the protein sampled the conformation space randomly. Because of the relevant timescales, if the protein randomly sampled conformation space, a protein would not be able to correctly fold in a person's lifetime. Herein lies the paradox, since properly folded proteins are needed for the person to exist in the first place.

Possible Solution

Because of the paradox, it becomes obvious that the protein cannot sample conformation space in a random fashion. Instead, the protein samples the space in a way consistant with statistical mechanics. The probability of sampling a given conformation is weighed by the energy of the conformation. Currently, the generally accepted idea in the field of protein folding is to consider an energy landscape, where every possible conformation is represented by an energy value. The idea is that the energy landscape is generally funnel shaped, with the native conformation having the lowest energy. As the protein folds from its random coil conformation, it travels from conformation to conformation such that with each step, the total energy is lowered.


[1] Levinthal's Paradox

Keyword in references:

G. Lois, J. Blawzdziewicz, and C. S. O'Hern, "Protein folding on rugged energy landscapes: Conformational diffusion on fractal networks", Phys. Rev. E 81 (2010) 051907

Reliable Protein Folding on Complex Energy Landscapes: The Free Energy Reaction Path