Protein folding

From Free net encyclopedia

Protein folding is the process by which a protein structure assumes its functional shape or conformation. All protein molecules are heterogeneous unbranched chains of amino acids. By coiling and folding into a specific three-dimensional shape they are able to perform their biological function.

The reverse of this process is protein denaturation, whereby a native protein is caused to lose its functional conformation, and become an amorphous, and non-functional amino acid chain. Denatured proteins may lose their solubility, and precipitate, becoming insoluble solids. In some cases, denaturation is reversible, and proteins may refold. In many other cases, however, denaturation is irreversible.

1 Known facts about the process
2 Techniques for studying protein folding
3 See also
4 External links

[edit]

Known facts about the process

[edit]

The relationship between folding and amino acid sequence

The particular amino-acid sequence (or "primary structure") of a protein predisposes it to fold into its native conformation. Many proteins do so spontaneously during or after their synthesis inside cells. While these macromolecules may be seen as "folding themselves," in fact their folding depends a great deal on the characteristics of their surrounding solution, including the identity of the primary solvent (either water or lipid inside cells), the concentration of salts, the temperature, and molecular chaperones.

For the most part, scientists have been able to study many identical molecules folding together en masse. It appears that in transitioning to the native state, a given amino acid sequence always takes roughly the same route and proceeds through roughly the same number of fundamental intermediates. At the coarsest level, folding involves first the establishment of secondary structure, particularly alpha helices and beta sheets, and only afterwards tertiary structure (formation of quaternary structure appears to involve the "assembly" or "coassembly" of subunits that have already folded). Unlike primary, secondary or quaternary structure, tertiary structure may involve covalent bonding in the form of disulfide bridges formed between two cysteine residues. This is unusual since the electrostatic interactions ( hydrogen bonding, Van der Waals interactions) between amino acid R groups usually mediate folding. Shortly before settling into their more stable native conformation, molecules appear to pass through an additional "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: Folding is a spontaneous process. The passage of the folded state is mainly guided by Van der Waals forces and entropic contributions to the Gibbs free energy: an increase in entropy is achieved by moving the hydrophobic parts of the protein inwards, and the hydrophilic ones outwards. This endows surrounding water molecules with more degrees of freedom. During the folding process, the number of hydrogen bonds does not change appreciably, because for every internal hydrogen bond in the protein, a hydrogen bond of the unfolded protein with the aqueous medium has to be broken.

[edit]

Preconditions for correct folding

In certain solutions and under some conditions proteins will not fold at all. Temperatures above or below the range that cells tend to live in will cause proteins to unfold or "denature" (this is why boiling makes the white of an egg opaque). High concentrations of solutes and extremes of pH can do the same. A fully denatured protein lacks both tertiary and secondary structure, and exists as a so-called random coil. Cells sometimes protect their proteins against the denaturing influence of heat with enzymes known as chaperones or heat shock proteins, which assist other proteins both in folding and in remaining folded. Some proteins never fold in cells at all except with the assistance of chaperone molecules, that isolate individual proteins so that their folding is not interrupted by interactions with other proteins. DNA conformation is maintained by another set of enzymes: the topoisomerases.

[edit]

Incorrect protein folding and neurodegenerative disease

Incorrectly folded proteins are responsible for prion related illness such as Creutzfeldt-Jakob disease and Bovine spongiform encephalopathy (mad cow disease), and amyloid related illnesses such as Alzheimer's Disease. These diseases are associated with the aggregation of misfolded proteins into insoluble plaques; it is not known whether the plaques are the cause or merely a symptom of illness.

[edit]

Time scales of protein folding

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 steric hindrances. However, small proteins, with lengths of a hundred or so amino acids, typically fold on time scales of milliseconds. The very fastest known protein folding reactions are complete within a few microseconds.

Folding and unfolding rates also depend on environment conditions like temperature, solvent viscosity, pH and more. The folding process can also be slowed down (and the unfolding sped up) by applying mechanical forces, as revealed by single-molecule experiments.

[edit]

Techniques for studying protein folding

[edit]

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, Martin Gruebele, Brian Dyer, William Eaton, and Bengt Nölting.

[edit]

Predicting energy landscapes: A theoretical approach

Since the late 1980s, a theoretical approach to understanding protein folding has been the calculation of protein energy landscapes. The energy landscape of a protein is the variation of its free energy as a function of its conformation, owing to the interactions between the amino acid residues. It has been proposed that natural proteins have evolved such that this complicated energy surface has a funnelled shape which leads towards the native state, which is the lowest-energy conformation available to the protein. 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 computational simulations of model proteins and has been used to improve methods for protein structure prediction and design.

[edit]

Computational prediction of protein tertiary structure

De novo or ab initio techniques for computational protein structure prediction employ simulations of protein folding to determine the protein's final folded shape.

[edit]

Imaging techniques for determination of protein structure

The determination of the folded structure of a protein is a lengthy and complicated process, involving methods like X-ray crystallography and NMR. In bioinformatics, one of the major areas of interest is the prediction of native structure from amino-acid sequences alone.

[edit]