Levinthal's paradox

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Levinthal's paradox is a thought experiment, also constituting a self-reference in the

theory of protein folding. In 1969, Cyrus Levinthal noted that, because of the very
large number of degrees of freedom in an unfolded polypeptide chain, the molecule
has an astronomical number of possible conformations. An estimate of 3300 or 10143
was made in one of his papers.[1] (Often incorrectly cited as a 1968 paper.[2]) For
example, a polypeptide of 100 residues will have 99 peptide bonds, and therefore 198
different phi and psi bond angles. If each of these bond angles can be in one of three
stable conformations, the protein may misfold into a maximum of 3198 different
conformations (including any possible folding redundancy). Therefore if a protein
were to attain its correctly folded configuration by sequentially sampling all the
possible conformations, it would require a time longer than the age of the universe to
arrive at its correct native conformation. This is true even if conformations are
sampled at rapid (nanosecond or picosecond) rates. The "paradox" is that most small
proteins fold spontaneously on a millisecond or even microsecond time scale. This
paradox is central to computational approaches to protein structure prediction.[3]

Levinthal himself was aware that proteins fold spontaneously and on short timescales.
He suggested that the paradox can be resolved if "protein folding is sped up and
guided by the rapid formation of local interactions which then determine the further
folding of the peptide; this suggests local amino acid sequences which form stable
interactions and serve as nucleation points in the folding process."[4] Indeed, the
protein folding intermediates and the partially folded transition states were
experimentally detected, which explains the fast protein folding. This is also
described as protein folding directed within funnel-like energy landscapes[5][6][7] Some
computational approaches to protein structure prediction have sought to identify and
simulate the mechanism of protein folding.[8]

Levinthal also suggested that the native structure might have a higher energy, if the
lowest energy was not kinetically accessible. An analogy is a rock tumbling down a
hillside that lodges in a gully rather than reaching the base.[9]

Contents
1 Suggested explanations
2 See also
3 References
4 External links

Suggested explanations
According to Edward Trifonov and Igor Berezovsky,[10] the proteins fold by
subunits (modules) of the size of 25-30 amino acids.
See also
Chaperone proteins that assist other proteins in folding or unfolding
Folding funnel
Anfinsen's dogma

References
1. Levinthal, Cyrus (1969). "How to Fold Graciously". Mossbauer
Spectroscopy in Biological Systems: Proceedings of a meeting held at Allerton
House, Monticello, Illinois: 2224. Archived from the original on 2010-10-07.
2. Levinthal, Cyrus (1968). "Are there pathways for protein folding?"
(PDF). Journal de Chimie Physique et de Physico-Chimie Biologique 65: 44
45. Archived from the original (PDF) on 2009-09-02.
3. Zwanzig R, Szabo A, Bagchi B (1992-01-01). "Levinthal's paradox".
Proc Natl Acad Sci USA 89 (1): 2022. doi:10.1073/pnas.89.1.20.
PMC 48166. PMID 1729690.
4. Rooman, Marianne Rooman; Yves Dehouck; Jean Marc Kwasigroch;
Christophe Biot; Dimitri Gilis (2002). "What is paradoxical about Levinthal
Paradox?" (PDF). Journal of Biomolecular Structure and Dynamics 20 (3):
327329. doi:10.1080/07391102.2002.10506850. PMID 12437370.
5. Dill K & H.S. Chan (1997). "From Levinthal to pathways to funnels".
Nat. Struct. Biol. 4 (1): 1019. doi:10.1038/nsb0197-10. PMID 8989315.
6. Durup, Jean (1998). "On "Levinthal paradox" and the theory of
protein folding". Journal of Molecular Structure 424 (12): 157169.
doi:10.1016/S0166-1280(97)00238-8.
7. sAli, Andrej; Shakhnovich, Eugene; Karplus, Martin (1994). "How
does a protein fold?" (PDF). Nature 369 (6477): 248251.
doi:10.1038/369248a0. PMID 7710478.
8. Karplus, Martin (1997). "The Levinthal paradox: yesterday and
today". Folding and Design 2 (4): S69S75. doi:10.1016/S1359-
0278(97)00067-9. PMID 9269572.
9. Hunter, Philip (2006). "Into the fold". EMBO Rep. 7 (3): 249252.
doi:10.1038/sj.embor.7400655. PMC 1456894. PMID 16607393.
10. Berezovsky, Igor N.; Trifonov, Edward N. (2002). "Loop fold structure
of proteins: Resolution of Levinthal's paradox" (PDF). Journal of
Biomolecular Structure & Dynamics 20 (1): 56.
doi:10.1080/07391102.2002.10506817. ISSN 0739-1102.

External links
http://www-wales.ch.cam.ac.uk/~mark/levinthal/levinthal.html
http://www.wired.com/wired/archive/9.07/blue_pr.html
 http://web.archive.org/web/20041011182039/http://www.sdsc.edu/~nair/levint
hal.html

Categories:
Protein structure
Physical paradoxes

Thought experiments