Protein folding

Known facts about the process

The relationship between folding and amino acid sequence

The amino-acid sequence (or chaperones.

Most folded proteins have a hydrophobic core in which side chain packing stabilizes the folded state, and charged or polar side chains on the solvent-exposed surface where they interact with surrounding water molecules. It is generally accepted that minimizing the number of hydrophobic sidechains exposed to water is the principal driving force behind the folding process,^[5] although a recent theory has been proposed which reassesses the contributions made by hydrogen bonding.^[6]

The process of folding in vivo often begins heat shock proteins. Although most globular proteins are able to assume their native state unassisted, chaperone-assisted folding is often necessary in the crowded intracellular environment to prevent aggregation; chaperones are also used to prevent misfolding and aggregation which may occur as a consequence of exposure to heat or other changes in the cellular environment.

For the most part, scientists have been able to study many identical molecules folding together en masse. At the coarsest level, it appears that in transitioning to the native state, a given amino acid sequence takes on roughly the same route and proceeds through roughly the same intermediates and transition states. Often folding involves first the establishment of regular secondary and supersecondary structures, particularly molten globule" state.

The essential fact of folding, however, remains that the amino acid sequence of each protein contains the information that specifies both the native structure and the pathway to attain that state. This is not to say that identical amino acid sequences always fold similarly^[8]. Conformations differ based on environmental factors as well; similar proteins fold differently based on where they are found. Folding is a van der Waals forces, and it is opposed by conformational entropy, which must be overcome by extrinsic factors such as chaperones.

Disruption of the native state

In certain solutions and under some conditions proteins will not fold into their biochemically functional forms. Temperatures above (and sometimes those below) the range that cells tend to live in will cause proteins to unfold or "precipitation into insoluble amorphous aggregates.

Incorrect protein folding and neurodegenerative disease

Misfolded proteins are responsible for amyloid-related illnesses such as Alzheimer's Disease, and a number of other forms of proteopathy such as cystic fibrosis. These diseases are associated with the multimerization of misfolded proteins into insoluble, extracellular aggregates and/or intracellular inclusions; it is not clear whether the plaques are the cause or merely a symptom of illness.

Kinetics and the Levinthal Paradox

The entire duration of the folding process varies dramatically depending on the protein of interest. The slowest folding proteins require many minutes or hours to fold, primarily due to proline isomerizations or wrong disulfide bond formations, and must pass through a number of intermediate states, like checkpoints, before the process is complete.^[10] On the other hand, very small single-domain proteins with lengths of up to a hundred amino acids typically fold in a single step.^[11] Time scales of milliseconds are the norm and the very fastest known protein folding reactions are complete within a few microseconds.^[12]

The Levinthal paradox^[13] observes that if a protein were to fold by sequentially sampling all possible conformations, it would take an astronomical amount of time to do so, even if the conformations were sampled at a rapid rate (on the nanosecond or picosecond scale). Based upon the observation that proteins fold much faster than this, Levinthal then proposed that a random conformational search does not occur in folding, and the protein must, therefore, fold by a directed process.

Techniques for studying protein folding

Modern studies of folding with high time resolution

The study of protein folding has been greatly advanced in recent years by the development of fast, time-resolved techniques. These are experimental methods for rapidly triggering the folding of a sample of unfolded protein, and then observing the resulting dynamics. Fast techniques in widespread use include ultrafast mixing of solutions, photochemical methods, and laser temperature jump spectroscopy. Among the many scientists who have contributed to the development of these techniques are Heinrich Roder, Harry Gray, Martin Gruebele, Brian Dyer, William Eaton, Sheena Radford, Chris Dobson, Sir Alan R. Fersht and Bengt Nölting.

Energy landscape theory of protein folding

The protein folding phenomenon was largely an experimental endeavor until the formulation of energy landscape theory by Joseph Bryngelson and Peter Wolynes in the late 1980s and early 1990s. This approach introduced the principle of minimal frustration, which asserts that evolution has selected the amino acid sequences of natural proteins so that interactions between side chains largely favor the molecule's acquisition of the folded state. Interactions that do not favor folding are selected against, although some residual frustration is expected to exist. A consequence of these evolutionarily selected sequences is that proteins are generally thought to have globally "funneled energy landscapes" (coined by José Onuchic) that are largely directed towards the native state. This "folding funnel" landscape allows the protein to fold to the native state through any of a large number of pathways and intermediates, rather than being restricted to a single mechanism. The theory is supported by both design.

Computational prediction of protein tertiary structure

De novo or ab initio techniques for computational protein structure prediction, but is also capable of reproducing the folding pathways.^[14]

Because of the many possible ways of folding, there can be many possible structures. A peptide consisting of just five amino acids can fold into over 100 billion possible structures. ^[15]

Techniques for determination of protein structure

The determination of the folded structure of a protein is a lengthy and complicated process, involving methods like prediction of native structure from amino-acid sequences alone using bioinformatics and computational simulation methods.

There are distibuted computing projects which use idle CPU time of personal computers to solve problems such as protein folding or prediction of protein structure. People can run these programs on their computer or PlayStation 3 to support them. See links below (for example Folding@Home) to get information about how to participate in these projects.

See also

• Folding (chemistry)
• Anfinsen's dogma
• Levinthal paradox
• Denaturation (biochemistry)
• Protein design
• Molecular modelling
• Chevron plot
• Denaturation midpoint
• Equilibrium unfolding
• Folding@Home
• Downhill folding

References

v • d • e Quaternary structure→

v • d • e Proteins
Proteasome Globular protein - Fibrous protein