Anfinsen's dogma

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ribonuclease A

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

ribonuclease A.[3][4]
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

chaperones
.

Some proteins need the assistance of chaperone proteins 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.[5]

Many proteins can also undergo aggregation and

misfolding. For example, prions 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 Alzheimer's disease and Parkinson's disease, are also exceptions to Anfinsen's dogma.[6]

Some proteins have

local minimum of free energy.[8]

References

  1. PMID 4124164
    .
  2. ^ "Press Release: The 1972 Nobel Prize in Chemistry". Nobelprize.org (Press release).
  3. PMID 13784818
    .
  4. PMID 13683522
    .
  5. S2CID 6435829. Archived from the original
    (PDF) on 2012-05-23.
  6. ^ "Protein Folding and Misfolding". Yale University Rhoades Lab. Archived from the original on 2012-07-19. Retrieved 2012-08-24.
  7. PMID 29784778
    .
  8. PMID 31390019
    .

Further reading
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