Anfinsen's dogma, also known as the thermodynamic hypothesis, is a postulate in molecular biology. It states that, at least for a small globular protein in its standard physiological environment, the

native structure Native may refer to: People * Jus soli, citizenship by right of birth * Indigenous peoples, peoples with a set of specific rights based on their historical ties to a particular territory ** Native Americans (disambiguation) In arts and enterta ...

is determined only by the protein's amino acid sequence. The dogma was championed by the Nobel Prize Laureate

Christian B. Anfinsen Christian Boehmer Anfinsen Jr. (March 26, 1916 – May 14, 1995) was an American biochemist. He shared the 1972 Nobel Prize in Chemistry with Stanford Moore and William Howard Stein for work on ribonuclease, especially concerning the conne ...

from his research on the folding of ribonuclease A. The postulate amounts to saying that, at the environmental conditions (temperature, solvent concentration and composition, etc.) at which folding occurs, the native structure is a unique, stable and kinetically accessible minimum of the free energy. In other words, there are three conditions for formation of a unique protein structure: *Uniqueness – Requires that the sequence does not have any other configuration with a comparable free energy. Hence the free energy minimum must be ''unchallenged''. *Stability – Small changes in the surrounding environment cannot give rise to changes in the minimum configuration. This can be pictured as a free energy surface that looks more like a funnel (with the native state in the bottom of it) rather than like a soup plate (with several closely related low-energy states); the free energy surface around the native state must be rather steep and high, in order to provide stability. *Kinetical accessibility – Means that the path in the free energy surface from the unfolded to the folded state must be reasonably smooth or, in other words, that the folding of the chain must not involve highly complex changes in the shape (like knots or other high order conformations).

Challenges to Anfinsen's dogma

Protein folding in a cell is a highly complex process that involves transport of the newly synthesized proteins to appropriate cellular compartments through targeting, permanent misfolding, temporarily unfolded states,

post-translational modifications Post-translational modification (PTM) is the covalent and generally enzymatic modification of proteins following protein biosynthesis. This process occurs in the endoplasmic reticulum and the golgi apparatus. Proteins are synthesized by ribosomes ...

, quality control, and formation of protein complexes facilitated by chaperones. Some proteins need the assistance of

chaperone protein In molecular biology, molecular chaperones are proteins that assist the conformational folding or unfolding of large proteins or macromolecular protein complexes. There are a number of classes of molecular chaperones, all of which function to assi ...

s to fold properly. It has been suggested that this disproves Anfinsen's dogma. However, the chaperones do not appear to affect the final state of the protein; they seem to work primarily by preventing

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of several protein molecules prior to the final folded state of the protein. However, at least some chaperones are required for the proper folding of their subject proteins. Many proteins can also undergo aggregation and misfolding. For example,

prion Prions are misfolded proteins that have the ability to transmit their misfolded shape onto normal variants of the same protein. They characterize several fatal and transmissible neurodegenerative diseases in humans and many other animals. It ...

s are stable conformations of proteins which differ from the native folding state. In bovine spongiform encephalopathy, native proteins re-fold into a different stable conformation, which causes fatal amyloid buildup. Other amyloid diseases, including

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and Parkinson's disease, are also exceptions to Anfinsen's dogma. Some proteins have multiple native structures, and change their fold based on some external factors. For example, the KaiB protein complex switches fold throughout the day, acting as a clock for cyanobacteria. It has been estimated that around 0.5–4% of PDB proteins switch folds. The switching between alternative structures is driven by interactions of the protein with small ligands or other proteins, by chemical modifications (such as

phosphorylation In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...

) or by changed environmental conditions, such as temperature, pH or

membrane potential Membrane potential (also transmembrane potential or membrane voltage) is the difference in electric potential between the interior and the exterior of a biological cell. That is, there is a difference in the energy required for electric charges ...

. Each alternative structure may either correspond to the global minimum of free energy of the protein at the given conditions or be kinetically trapped in a higher local minimum of free energy.

Challenges to Anfinsen's dogma

References

Further reading