The alpha helix (α-helix) is a common secondary structure of proteins. It is a right- or left-handed coiled conformation, resembling a spring, in which every backbone N-H group donates a hydrogen bond to the backbone C=O group of the amino acid four residues earlier ( hydrogen bonding). This secondary structure is also sometimes called a classic Pauling-Corey-Branson alpha helix.
Secondary structure is the general three-dimensional form of local segments of biopolymers such as proteins and nucleic acids (DNA/RNA). It does not, however, describe specific atomic positions in three-dimensional space, which are considered to be tertiary structure.
An alpha helix (α-helix) is a twisted part of a protein. It is one of the two most common parts of the secondary structure, or shape, of a protein. The other is the beta sheet. An alpha helix is created by alternating groups of atoms. There is a carbonyl group, created by a carbon atom double bonded to an oxygen atom, and an amine group, created by a nitrogen atom bonded to a hydrogen atom. Each section containing one of each of these groups is called a residue, a general term for a small part of a molecule. Each amine group forms a hydrogen bond with the carbonyl group four residues earlier. A prion is a protein that causes disease by changing the shape of another protein. It does this by changing some of the alpha helices, which are more common in normal cells, to beta sheets, which are more common in prions. The alpa helix consits of 3.6 residues per turn. All hydrogen bonds face in the same direction.
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In the early 1930s, William Astbury showed that there were drastic changes in the X-ray fiber diffraction of moist wool or hair fibers upon significant stretching. The data suggested that the unstretched fibers had a coiled molecular structure with a characteristic repeat of ~5.1 ångströms (0.51 nm).
Astbury initially proposed a kinked-chain structure for the fibers. He later joined other researchers (notably the American chemist Maurice Huggins) in proposing that:
- the unstretched protein molecules formed a helix (which he called the α-form); and
- the stretching caused the helix to uncoil, forming an extended state (which he called the β-form).
Although incorrect in their details, Astbury's models of these forms were correct in essence and correspond to modern elements of secondary structure, the α-helix and the β-strand (Astbury's nomenclature was kept), which were developed by Linus Pauling, Robert Corey and Herman Branson in 1951. Hans Neurath was the first to show that Astbury's models could not be correct in detail, because they involved clashes of atoms. Neurath's paper and Astbury's data inspired H. S. Taylor, Maurice Huggins and Bragg and collaborators to propose models of keratin that resemble the modern α-helix.
Two key developments in the modeling of the modern α-helix were (1) the correct bond geometry, thanks to the crystal structure determinations of amino acids and peptides and Pauling's prediction of planar peptide bonds; and (2) the relinquishing of the assumption of an integral number of residues per turn of the helix. The pivotal moment came in the early spring of 1948, when Pauling caught a cold and went to bed. Being bored, he drew a polypeptide chain of roughly correct dimensions on a strip of paper and folded it into a helix, being careful to maintain the planar peptide bonds. After a few attempts, he produced a model with physically plausible hydrogen bonds. Pauling then worked with Corey and Branson to confirm his model before publication.
Helices observed in proteins can range from four to over forty residues long, but a typical helix contains about ten amino acids (about three turns). Short polypeptides generally do not exhibit much alpha helical structure in solution, since the entropic cost associated with the folding of the polypeptide chain is not compensated for by a sufficient amount of stabilizing interactions. The backbone hydrogen bonds of α-helices are generally considered slightly weaker than those found in β-sheets, and are readily attacked by the ambient water molecules. However, in more hydrophobic environments such as the plasma membrane, or in the presence of co-solvents such as trifluoroethanol (TFE), or isolated from solvent in the gas phase, oligopeptides readily adopt stable α-helical structure.
Since the α-helix is defined by its hydrogen bonds, the most reliable experimental methods for determining an α-helix involve an atomic-resolution structure provided by X-ray crystallography or NMR spectroscopy. In some cases, the individual hydrogen bonds can be observed directly as a small scalar coupling in NMR.
Different amino-acid sequences have different propensities for forming α-helical structure. Methionine, alanine, leucine, uncharged glutamate, and lysine ("MALEK" in the amino-acid 1-letter codes) all have especially high helix-forming propensities, whereas proline, glycine and negatively charged aspartate have poor helix-forming propensities. Proline tends to break or kink helices because it cannot donate an amide hydrogen bond (having no amide hydrogen), and because its sidechain interferes sterically; its ring structure also restricts its backbone φ dihedral angle to the vicinity of -70°, which is less common in α-helices. However, proline is often seen as the first residue of a helix, presumably due to its structural rigidity. At the other extreme, glycine also tends to disrupt helices because its high conformational flexibility makes it entropically expensive to adopt the relatively constrained α-helical structure.
A helix has an overall dipole moment caused by the aggregate effect of all the individual dipoles from the carbonyl groups of the peptide bond pointing along the helix axis. This can lead to destabilization of the helix through entropic effects. As a result, α helices are often capped at the N-terminal end by a negatively charged amino acid, such as glutamic acid, in order to neutralize this helix dipole. Less common (and less effective) is C-terminal capping with a positively charged amino acid, such as lysine. The N-terminal positive charge is commonly used to bind negatively charged ligands such as phosphate groups, which is especially effective because the backbone amides can serve as hydrogen bond donors.
Myoglobin, the first protein whose structure was solved by X-ray crystallography, is made up of about 70% α helix, with the rest being loops or disordered regions. In classifying proteins by their dominant fold, the Structural Classification of Proteins database maintains a category specifically for all-α proteins.
α helices have particular significance in DNA binding motifs, including helix-turn-helix motifs, leucine zipper motifs and zinc finger motifs. This is because of the convenient structural fact that the diameter of the α helix is 1.2 nanometres, the same as the width of the major groove in B-form DNA.
Homopolymers of amino-acids (such as poly-lysine) can adopt α-helical structure at low temperature that is "melted out" at high temperatures. This helix-coil transition was once thought to be analogous to protein denaturation. The statistical mechanics of this transition can be modeled using an elegant transfer matrix method, characterized by two parameters: the propensity to initiate a helix and the propensity to extend a helix.
The β sheet (also β-pleated sheet) is the second form of regular secondary structure in proteins consisting of beta strands connected laterally by five or more hydrogen bonds, forming a generally twisted, pleated sheet (the most common form of regular secondary structure in proteins is the alpha helix). A beta strand (also β-strand) is a stretch of amino acids typically 5–10 amino acids long whose peptide backbones are almost fully extended. The association of beta sheets has been implicated in the formation of protein aggregates and fibrils observed in many human diseases, notably the amyloidoses.
A helix bundle is a small protein fold composed of several alpha helices that are usually nearly parallel or antiparallel to each other.
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