Levinthal's paradox is a
thought experiment
A thought experiment is a hypothetical situation in which a hypothesis, theory, or principle is laid out for the purpose of thinking through its consequences.
History
The ancient Greek ''deiknymi'' (), or thought experiment, "was the most anc ...
, also constituting a
self-reference in the theory of
protein folding
Protein folding is the physical process by which a protein chain is translated to its native three-dimensional structure, typically a "folded" conformation by which the protein becomes biologically functional. Via an expeditious and reproduc ...
. In 1969,
Cyrus Levinthal noted that, because of the very large number of
degrees of freedom in an unfolded
polypeptide chain
Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides.
...
, the molecule has an astronomical number of possible conformations. An estimate of 10
300 was made in one of his papers (often incorrectly cited as the 1968 paper). 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 3
198 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
A nanosecond (ns) is a unit of time in the International System of Units (SI) equal to one billionth of a second, that is, of a second, or 10 seconds.
The term combines the SI prefix ''nano-'' indicating a 1 billionth submultiple of an SI unit ( ...
or
picosecond) rates. The "paradox" is that most small proteins fold spontaneously on a millisecond or even microsecond time scale. The solution to this paradox has been established by computational approaches to
protein structure prediction
Protein structure prediction is the inference of the three-dimensional structure of a protein from its amino acid sequence—that is, the prediction of its secondary and tertiary structure from primary structure. Structure prediction is different ...
.
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". Indeed, the protein folding
intermediates and the partially folded
transition state
In chemistry, the transition state of a chemical reaction is a particular configuration along the reaction coordinate. It is defined as the state corresponding to the highest potential energy along this reaction coordinate. It is often marked ...
s were experimentally detected, which explains the fast
protein folding
Protein folding is the physical process by which a protein chain is translated to its native three-dimensional structure, typically a "folded" conformation by which the protein becomes biologically functional. Via an expeditious and reproduc ...
. This is also described as protein folding directed within
funnel-like energy landscapes. Some computational approaches to protein structure prediction have sought to identify and simulate the mechanism of protein folding.
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.
Suggested explanations
* According to
Edward Trifonov
Edward Nikolayevich Trifonov ( he, אדוארד טריפונוב, russian: Эдуapд Тpифoнoв; b. March 31, 1937) is a Russian-born Israeli molecular biophysicist and a founder of Israeli bioinformatics. In his research, he specializes in ...
and Igor Berezovsky, 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
The folding funnel hypothesis is a specific version of the energy landscape theory of protein folding, which assumes that a protein's native state corresponds to its free energy minimum under the solution conditions usually encountered in cells. A ...
*
Anfinsen's dogma
References
External links
* http://www-wales.ch.cam.ac.uk/~mark/levinthal/levinthal.html
* https://www.wired.com/wired/archive/9.07/blue_pr.html
* https://web.archive.org/web/20041011182039/http://www.sdsc.edu/~nair/levinthal.html
{{DEFAULTSORT:Levinthal's Paradox
Protein structure
Physical paradoxes
Thought experiments