Anfinsen's dogma, also known as the thermodynamic hypothesis, is a postulate in

molecular biology Molecular biology is a branch of biology that seeks to understand the molecule, molecular basis of biological activity in and between Cell (biology), cells, including biomolecule, biomolecular synthesis, modification, mechanisms, and interactio ...

. It states that, at least for a small

globular protein In biochemistry, globular proteins or spheroproteins are spherical ("globe-like") proteins and are one of the common protein types (the others being fibrous, disordered and membrane proteins). Globular proteins are somewhat water-soluble (form ...

in its standard physiological environment, the native structure is determined only by the protein's

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...

sequence In mathematics, a sequence is an enumerated collection of objects in which repetitions are allowed and order matters. Like a set, it contains members (also called ''elements'', or ''terms''). The number of elements (possibly infinite) is cal ...

. The

dogma Dogma, in its broadest sense, is any belief held definitively and without the possibility of reform. It may be in the form of an official system of principles or doctrines of a religion, such as Judaism, Roman Catholicism, Protestantism, or Islam ...

was championed by the Nobel Prize Laureate Christian B. Anfinsen from his research on the folding of

ribonuclease A Pancreatic ribonuclease family (, ''RNase'', ''RNase I'', ''RNase A'', ''pancreatic RNase'', ''ribonuclease I'', ''endoribonuclease I'', ''ribonucleic phosphatase'', ''alkaline ribonuclease'', ''ribonuclease'', ''gene S glycoproteins'', ''Cerati ...

. His research was based on previous studies by biochemist Lisa Steiner, whose superiors at the time did not recognize the significance. 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). Basic changes in the shape of the protein happen dependent on their environment, shifting shape to suit their place. This creates multiple configurations for biomolecules to shift into.

Challenges to Anfinsen's dogma

Protein folding Protein folding is the physical process by which a protein, after Protein biosynthesis, synthesis by a ribosome as a linear chain of Amino acid, amino acids, changes from an unstable random coil into a more ordered protein tertiary structure, t ...

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 In molecular biology, post-translational modification (PTM) is the covalent process of changing proteins following protein biosynthesis. PTMs may involve enzymes or occur spontaneously. Proteins are created by ribosomes, which translation (biolog ...

, quality control, and formation of

protein complexes A protein complex or multiprotein complex is a group of two or more associated polypeptide chains. Protein complexes are distinct from multidomain enzymes, in which multiple catalytic domains are found in a single polypeptide chain. Protein c ...

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 aggregation 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 A prion () is a Proteinopathy, misfolded protein that induces misfolding in normal variants of the same protein, leading to cellular death. Prions are responsible for prion diseases, known as transmissible spongiform encephalopathy (TSEs), w ...

s are stable conformations of proteins which differ from the native folding state. In

bovine spongiform encephalopathy Bovine spongiform encephalopathy (BSE), commonly known as mad cow disease, is an incurable and always fatal neurodegenerative disease of cattle. Symptoms include abnormal behavior, trouble walking, and weight loss. Later in the course of th ...

, native proteins re-fold into a different stable conformation, which causes fatal

amyloid Amyloids are aggregates of proteins characterised by a fibrillar morphology of typically 7–13 nm in diameter, a β-sheet secondary structure (known as cross-β) and ability to be stained by particular dyes, such as Congo red. In the human ...

buildup. Other amyloid diseases, including

Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...

and

Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a neurodegenerative disease primarily of the central nervous system, affecting both motor system, motor and non-motor systems. Symptoms typically develop gradually and non-motor issues become ...

, 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

Protein Data Bank The Protein Data Bank (PDB) is a database for the three-dimensional structural data of large biological molecules such as proteins and nucleic acids, which is overseen by the Worldwide Protein Data Bank (wwPDB). This structural data is obtained a ...

(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 biochemistry, phosphorylation is described as the "transfer of a phosphate group" from a donor to an acceptor. A common phosphorylating agent (phosphate donor) is ATP and a common family of acceptor are alcohols: : This equation can be writ ...

) 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. It equals the interior potential minus the exterior potential. This is th ...

. 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 In mathematical analysis, the maximum and minimum of a function are, respectively, the greatest and least value taken by the function. Known generically as extremum, they may be defined either within a given range (the ''local'' or ''relative ...

of free energy.

Challenges to Anfinsen's dogma

References

Further reading