Protein folding

The native fold can often be predicted on the basis of homology . This is a powerful tool in the prediction of protein structure, as it appears that although the number of actual proteins is vast, they are generally composed of one or more specific protein folds . It has been suggested that there are only around 2000 distinct protein folds in nature! This fact allows many proteins to be putativly assigned a structure by homology modeling .

In the case that no clear homology is present between a protein sequence of unknown structure and a sequence of known structure, the queried protein may be screened against each known fold (from a fold library ), and the most 'parsimonious' fold selected.

A very important tool in the identification of distinct protein folds is structural alignment.

The particular amino-acid sequence (or " primary structure ") ofa 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 characteristicsof their surrounding solution, including the identity of the primary solvent (either water or lipid inside cells), the concentration of salts, and the temperature.

For the most part, scientists have been able to study only 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 only afterwards tertiary structure (formation of quaternary structure appears to involve the "assembly" or "co-assembly" of subunits that have already folded). Shortly before settling into their more stable native conformation, molecules appear to pass through an additional " molten globule " state. The entire process from fully denatured to fully folded lasts a few tens of milliseconds.

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 shockproteins , 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. Folding is a spontaneous process that 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 amount 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.

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.

 

 

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