Alpha helix

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Three-dimensional structure of an alpha helix in the protein crambin Polypeptide forming an alpha helix, with hydrogen bonds in magenta.gif
Three-dimensional structure of an alpha helix in the protein crambin

The alpha helix (α-helix) is a common motif in the secondary structure of proteins and is a right hand-helix conformation in which every backbone N−H group hydrogen bonds to the backbone C=O group of the amino acid located four residues earlier along the protein sequence.

Contents

The alpha helix is also called a classic Pauling–Corey–Branson α-helix. The name 3.613-helix is also used for this type of helix, denoting the average number of residues per helical turn, with 13 atoms being involved in the ring formed by the hydrogen bond.

Among types of local structure in proteins, the α-helix is the most extreme and the most predictable from sequence, as well as the most prevalent.

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Interactive diagram of hydrogen bonds in protein secondary structure. Cartoon above, atoms below with nitrogen in blue, oxygen in red (PDB: 1AXC ) Alpha beta structure (2).png
The image above contains clickable links Interactive icon.svg
The image above contains clickable links
Interactive diagram of hydrogen bonds in protein secondary structure. Cartoon above, atoms below with nitrogen in blue, oxygen in red ( PDB: 1AXC​ )

Discovery

Alpha helix neg60 neg45 sideview.png
Side view of an α-helix of alanine residues in atomic detail. Two hydrogen bonds for the same peptide group are highlighted in magenta; the H to O distance is about 2 Å (0.20 nm). The protein chain runs upward here; that is, its N-terminus is at the bottom and its C-terminus at the top. Note that the sidechains (black stubs) angle slightly downward, toward the N-terminus, while the peptide oxygens (red) point up and the peptide NHs (blue with grey stubs) point down.
Alpha helix neg60 neg45 topview.png
Top view of the same helix shown above. Four carbonyl groups are pointing upwards toward the viewer, spaced roughly 100° apart on the circle, corresponding to 3.6 amino-acid residues per turn of the helix.

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 nanometres ).

Astbury initially proposed a linked-chain structure for the fibers. He later joined other researchers (notably the American chemist Maurice Huggins) in proposing that:

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 (see below); that paper showed both right- and left-handed helices, although in 1960 the crystal structure of myoglobin [1] showed that the right-handed form is the common one. Hans Neurath was the first to show that Astbury's models could not be correct in detail, because they involved clashes of atoms. [2] Neurath's paper and Astbury's data inspired H. S. Taylor, [3] Maurice Huggins [4] and Bragg and collaborators [5] to propose models of keratin that somewhat resemble the modern α-helix.

Two key developments in the modeling of the modern α-helix were: the correct bond geometry, thanks to the crystal structure determinations of amino acids and peptides and Pauling's prediction of planar peptide bonds; and his 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. [6] In 1954, Pauling was awarded his first Nobel Prize "for his research into the nature of the chemical bond and its application to the elucidation of the structure of complex substances" [7] (such as proteins), prominently including the structure of the α-helix.

Structure

Geometry and hydrogen bonding

The amino acids in an α-helix are arranged in a right-handed helical structure where each amino acid residue corresponds to a 100° turn in the helix (i.e., the helix has 3.6 residues per turn), and a translation of 1.5 Å (0.15 nm) along the helical axis. Dunitz [8] describes how Pauling's first article on the theme in fact shows a left-handed helix, the enantiomer of the true structure. Short pieces of left-handed helix sometimes occur with a large content of achiral glycine amino acids, but are unfavorable for the other normal, biological L-amino acids. The pitch of the alpha-helix (the vertical distance between consecutive turns of the helix) is 5.4 Å (0.54 nm), which is the product of 1.5 and 3.6. What is most important is that the N-H group of an amino acid forms a hydrogen bond with the C=O group of the amino acid four residues earlier; this repeated i + 4 → i hydrogen bonding is the most prominent characteristic of an α-helix. Official international nomenclature [9] [10] specifies two ways of defining α-helices, rule 6.2 in terms of repeating φ, ψ torsion angles (see below) and rule 6.3 in terms of the combined pattern of pitch and hydrogen bonding. The α-helices can be identified in protein structure using several computational methods, one of which is DSSP (Define  Secondary Structure of Protein). [11]

Contrast of helix end views between a (offset squarish) vs 310 (triangular) Alpha vs 310 helix end views.jpg
Contrast of helix end views between α (offset squarish) vs 310 (triangular)

Similar structures include the 310 helix (i + 3 → i hydrogen bonding) and the π-helix (i + 5 → i hydrogen bonding). The α-helix can be described as a 3.613 helix, since the i + 4 spacing adds three more atoms to the H-bonded loop compared to the tighter 310 helix, and on average, 3.6 amino acids are involved in one ring of α-helix. The subscripts refer to the number of atoms (including the hydrogen) in the closed loop formed by the hydrogen bond. [12]

Ramachandran plot (ph, ps plot), with data points for a-helical residues forming a dense diagonal cluster below and left of center, around the global energy minimum for backbone conformation. Ramachandran plot general 100K.jpg
Ramachandran plot (φ, ψ plot), with data points for α-helical residues forming a dense diagonal cluster below and left of center, around the global energy minimum for backbone conformation.

Residues in α-helices typically adopt backbone (φ, ψ) dihedral angles around (−60°, −45°), as shown in the image at right. In more general terms, they adopt dihedral angles such that the ψ dihedral angle of one residue and the φ dihedral angle of the next residue sum to roughly −105°. As a consequence, α-helical dihedral angles, in general, fall on a diagonal stripe on the Ramachandran diagram (of slope −1), ranging from (−90°, −15°) to (−35°, −70°). For comparison, the sum of the dihedral angles for a 310 helix is roughly −75°, whereas that for the π-helix is roughly −130°. The general formula for the rotation angle Ω per residue of any polypeptide helix with trans isomers is given by the equation [14] [15]

3 cos Ω = 1 − 4 cos2φ + ψ/2

The α-helix is tightly packed; there is almost no free space within the helix. The amino-acid side-chains are on the outside of the helix, and point roughly "downward" (i.e., toward the N-terminus), like the branches of an evergreen tree (Christmas tree effect). This directionality is sometimes used in preliminary, low-resolution electron-density maps to determine the direction of the protein backbone. [16]

Stability

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). In general, short polypeptides do not exhibit much α-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. In general, the backbone hydrogen bonds of α-helices are 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, [17] oligopeptides readily adopt stable α-helical structure. Furthermore, crosslinks can be incorporated into peptides to conformationally stabilize helical folds. Crosslinks stabilize the helical state by entropically destabilizing the unfolded state and by removing enthalpically stabilized "decoy" folds that compete with the fully helical state. [18] It has been shown that α-helices are more stable, robust to mutations and designable than β-strands in natural proteins, [19] and also in artificial designed proteins. [20]

An a-helix in ultrahigh-resolution electron density contours, with oxygen atoms in red, nitrogen atoms in blue, and hydrogen bonds as green dotted lines (PDB file 2NRL, 17-32). The N-terminus is at the top, here. Helix electron density myoglobin 2nrl 17-32.jpg
An α-helix in ultrahigh-resolution electron density contours, with oxygen atoms in red, nitrogen atoms in blue, and hydrogen bonds as green dotted lines (PDB file 2NRL, 17–32). The N-terminus is at the top, here.

Experimental determination

Since the α-helix is defined by its hydrogen bonds and backbone conformation, the most detailed experimental evidence for α-helical structure comes from atomic-resolution X-ray crystallography such as the example shown at right. It is clear that all the backbone carbonyl oxygens point downward (toward the C-terminus) but splay out slightly, and the H-bonds are approximately parallel to the helix axis. Protein structures from NMR spectroscopy also show helices well, with characteristic observations of nuclear Overhauser effect (NOE) couplings between atoms on adjacent helical turns. In some cases, the individual hydrogen bonds can be observed directly as a small scalar coupling in NMR.

There are several lower-resolution methods for assigning general helical structure. The NMR chemical shifts (in particular of the Cα, Cβ and C′) and residual dipolar couplings are often characteristic of helices. The far-UV (170–250 nm) circular dichroism spectrum of helices is also idiosyncratic, exhibiting a pronounced double minimum at around 208 and 222 nm. Infrared spectroscopy is rarely used, since the α-helical spectrum resembles that of a random coil (although these might be discerned by, e.g., hydrogen-deuterium exchange). Finally, cryo electron microscopy is now capable of discerning individual α-helices within a protein, although their assignment to residues is still an active area of research.

Long homopolymers of amino acids often form helices if soluble. Such long, isolated helices can also be detected by other methods, such as dielectric relaxation, flow birefringence, and measurements of the diffusion constant. In stricter terms, these methods detect only the characteristic prolate (long cigar-like) hydrodynamic shape of a helix, or its large dipole moment.

Amino-acid propensities

Different amino-acid sequences have different propensities for forming α-helical structure. Methionine, alanine, leucine, glutamate, and lysine uncharged ("MALEK" in the amino-acid 1-letter codes) all have especially high helix-forming propensities, whereas proline and glycine have poor helix-forming propensities. [21] Proline either breaks or kinks a helix, both because it cannot donate an amide hydrogen bond (having no amide hydrogen), and also because its sidechain interferes sterically with the backbone of the preceding turn  inside a helix, this forces a bend of about 30° in the helix's axis. [12] However, proline is often seen as the first residue of a helix, it is presumed 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.

Table of standard amino acid alpha-helical propensities

Estimated differences in free energy, Δ(ΔG), estimated in kcal/mol per residue in an α-helical configuration, relative to alanine arbitrarily set as zero. Higher numbers (more positive free energies) are less favoured. Significant deviations from these average numbers are possible, depending on the identities of the neighbouring residues.

Differences in free energy per residue [22]
Amino acid3-
letter
1-
letter
Helical penalty
kcal/mol kJ/mol
Alanine AlaA0.000.00
Arginine ArgR0.210.88
Asparagine AsnN0.652.72
Aspartic acid AspD0.692.89
Cysteine CysC0.682.85
Glutamic acid GluE0.401.67
Glutamine GlnQ0.391.63
Glycine GlyG1.004.18
Histidine HisH0.612.55
Isoleucine IleI0.411.72
Leucine LeuL0.210.88
Lysine LysK0.261.09
Methionine MetM0.241.00
Phenylalanine PheF0.542.26
Proline ProP3.1613.22
Serine SerS0.502.09
Threonine ThrT0.662.76
Tryptophan TrpW0.492.05
Tyrosine TyrY0.532.22
Valine ValV0.612.55

Dipole moment

A helix has an overall dipole moment due to the aggregate effect of the individual microdipoles from the carbonyl groups of the peptide bond pointing along the helix axis. [23] The effects of this macrodipole are a matter of some controversy. α-helices often occur with the N-terminal end bound by a negatively charged group, sometimes an amino acid side chain such as glutamate or aspartate, or sometimes a phosphate ion. Some regard the helix macrodipole as interacting electrostatically with such groups. Others feel that this is misleading and it is more realistic to say that the hydrogen bond potential of the free NH groups at the N-terminus of an α-helix can be satisfied by hydrogen bonding; this can also be regarded as set of interactions between local microdipoles such as C=O···H−N. [24] [25]

Coiled coils

Coiled-coil α helices are highly stable forms in which two or more helices wrap around each other in a "supercoil" structure. Coiled coils contain a highly characteristic sequence motif known as a heptad repeat , in which the motif repeats itself every seven residues along the sequence (amino acid residues, not DNA base-pairs). The first and especially the fourth residues (known as the a and d positions) are almost always hydrophobic; the fourth residue is typically leucine   this gives rise to the name of the structural motif called a leucine zipper , which is a type of coiled-coil. These hydrophobic residues pack together in the interior of the helix bundle. In general, the fifth and seventh residues (the e and g positions) have opposing charges and form a salt bridge stabilized by electrostatic interactions. Fibrous proteins such as keratin or the "stalks" of myosin or kinesin often adopt coiled-coil structures, as do several dimerizing proteins. A pair of coiled-coils  a four-helix bundle   is a very common structural motif in proteins. For example, it occurs in human growth hormone and several varieties of cytochrome. The Rop protein, which promotes plasmid replication in bacteria, is an interesting case in which a single polypeptide forms a coiled-coil and two monomers assemble to form a four-helix bundle.

Facial arrangements

The amino acids that make up a particular helix can be plotted on a helical wheel, a representation that illustrates the orientations of the constituent amino acids (see the article for leucine zipper for such a diagram). Often in globular proteins, as well as in specialized structures such as coiled-coils and leucine zippers, an α-helix will exhibit two "faces"  one containing predominantly hydrophobic amino acids oriented toward the interior of the protein, in the hydrophobic core, and one containing predominantly polar amino acids oriented toward the solvent-exposed surface of the protein.

Changes in binding orientation also occur for facially-organized oligopeptides. This pattern is especially common in antimicrobial peptides, and many models have been devised to describe how this relates to their function. Common to many of them is that the hydrophobic face of the antimicrobial peptide forms pores in the plasma membrane after associating with the fatty chains at the membrane core. [26] [27]

Larger-scale assemblies

The Hemoglobin molecule has four heme-binding subunits, each made largely of a-helices. 1GZX Haemoglobin.png
The Hemoglobin molecule has four heme-binding subunits, each made largely of α-helices.

Myoglobin and hemoglobin, the first two proteins whose structures were solved by X-ray crystallography, have very similar folds made up of about 70% α-helix, with the rest being non-repetitive regions, or "loops" that connect the helices. In classifying proteins by their dominant fold, the Structural Classification of Proteins database maintains a large category specifically for all-α proteins.

Hemoglobin then has an even larger-scale quaternary structure, in which the functional oxygen-binding molecule is made up of four subunits.

Functional roles

Leucine zipper coiled-coil helices & DNA-binding helices: transcription factor Max (PDB file 1HLO) Coiled-coil TF Max on DNA.jpg
Leucine zipper coiled-coil helices & DNA-binding helices: transcription factor Max (PDB file 1HLO)
Bovine rhodopsin (PDB file 1GZM), with a bundle of seven helices crossing the membrane (membrane surfaces marked by horizontal lines) 1gzm opm.png
Bovine rhodopsin (PDB file 1GZM), with a bundle of seven helices crossing the membrane (membrane surfaces marked by horizontal lines)

DNA binding

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 an α-helix is about 12 Å (1.2 nm) including an average set of sidechains, about the same as the width of the major groove in B-form DNA, and also because coiled-coil (or leucine zipper) dimers of helices can readily position a pair of interaction surfaces to contact the sort of symmetrical repeat common in double-helical DNA. [28] An example of both aspects is the transcription factor Max (see image at left), which uses a helical coiled coil to dimerize, positioning another pair of helices for interaction in two successive turns of the DNA major groove.

Membrane spanning

α-Helices are also the most common protein structure element that crosses biological membranes (transmembrane protein), [29] it is presumed because the helical structure can satisfy all backbone hydrogen-bonds internally, leaving no polar groups exposed to the membrane if the sidechains are hydrophobic. Proteins are sometimes anchored by a single membrane-spanning helix, sometimes by a pair, and sometimes by a helix bundle, most classically consisting of seven helices arranged up-and-down in a ring such as for rhodopsins (see image at right) or for G protein–coupled receptors (GPCRs). The structural stability between pairs of α-Helical transmembrane domains rely on conserved membrane interhelical packing motifs, for example, the Glycine-xxx-Glycine (or small-xxx-small) motif. [30]

Mechanical properties

α-Helices under axial tensile deformation, a characteristic loading condition that appears in many alpha-helix-rich filaments and tissues, results in a characteristic three-phase behavior of stiff-soft-stiff tangent modulus. [31] Phase I corresponds to the small-deformation regime during which the helix is stretched homogeneously, followed by phase II, in which alpha-helical turns break mediated by the rupture of groups of H-bonds. Phase III is typically associated with large-deformation covalent bond stretching.

Dynamical features

Alpha-helices in proteins may have low-frequency accordion-like motion as observed by the Raman spectroscopy [32] and analyzed via the quasi-continuum model. [33] [34] Helices not stabilized by tertiary interactions show dynamic behavior, which can be mainly attributed to helix fraying from the ends. [35]

Helix–coil transition

Homopolymers of amino acids (such as polylysine) 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.

In art

Julian Voss-Andreae's Alpha Helix for Linus Pauling (2004), powder coated steel, height 10 ft (3 m). The sculpture stands in front of Pauling's childhood home on 3945 SE Hawthorne Boulevard in Portland, Oregon, USA. AlphaHelixForLinusPauling.jpg
Julian Voss-Andreae's Alpha Helix for Linus Pauling (2004), powder coated steel, height 10 ft (3 m). The sculpture stands in front of Pauling's childhood home on 3945 SE Hawthorne Boulevard in Portland, Oregon, USA.

At least five artists have made explicit reference to the α-helix in their work: Julie Newdoll in painting and Julian Voss-Andreae, Bathsheba Grossman, Byron Rubin, and Mike Tyka in sculpture.

San Francisco area artist Julie Newdoll, [36] who holds a degree in Microbiology with a minor in art, has specialized in paintings inspired by microscopic images and molecules since 1990. Her painting "Rise of the Alpha Helix" (2003) features human figures arranged in an α helical arrangement. According to the artist, "the flowers reflect the various types of sidechains that each amino acid holds out to the world". [36] This same metaphor is also echoed from the scientist's side: "β sheets do not show a stiff repetitious regularity but flow in graceful, twisting curves, and even the α-helix is regular more in the manner of a flower stem, whose branching nodes show the influence of environment, developmental history, and the evolution of each part to match its own idiosyncratic function." [12]

Julian Voss-Andreae is a German-born sculptor with degrees in experimental physics and sculpture. Since 2001 Voss-Andreae creates "protein sculptures" [37] based on protein structure with the α-helix being one of his preferred objects. Voss-Andreae has made α-helix sculptures from diverse materials including bamboo and whole trees. A monument Voss-Andreae created in 2004 to celebrate the memory of Linus Pauling, the discoverer of the α-helix, is fashioned from a large steel beam rearranged in the structure of the α-helix. The 10-foot-tall (3 m), bright-red sculpture stands in front of Pauling's childhood home in Portland, Oregon.

Ribbon diagrams of α-helices are a prominent element in the laser-etched crystal sculptures of protein structures created by artist Bathsheba Grossman, such as those of insulin, hemoglobin, and DNA polymerase. [38] Byron Rubin is a former protein crystallographer now professional sculptor in metal of proteins, nucleic acids, and drug molecules  many of which featuring α-helices, such as subtilisin, human growth hormone, and phospholipase A2. [39]

Mike Tyka is a computational biochemist at the University of Washington working with David Baker. Tyka has been making sculptures of protein molecules since 2010 from copper and steel, including ubiquitin and a potassium channel tetramer. [40]

See also

Related Research Articles

Beta sheet Common motif of regular secondary structure in proteins; stretch of polypeptide chain typically 3 to 10 amino acids long with backbone in an extended conformation

The beta sheet, (β-sheet) is a common motif of the regular protein secondary structure. Beta sheets consist of beta strands (β-strands) connected laterally by at least two or three backbone hydrogen bonds, forming a generally twisted, pleated sheet. A β-strand is a stretch of polypeptide chain typically 3 to 10 amino acids long with backbone in an extended conformation. The supramolecular association of β-sheets has been implicated in the formation of the fibrils and protein aggregates observed in amyloidosis, notably Alzheimer's disease.

Collagen helix A structure in biochemistry

The collagen triple helix or type-2 helix is the primary secondary structure of various types of fibrous collagen, including type I collagen. It consists of a triple helix made of the repetitious amino acid sequence glycine-X-Y, where X and Y are frequently proline or hydroxyproline. Collagen folded into a triple helix is known as tropocollagen. Collagen triple helices are often bundled into fibrils which themselves form larger fibres, as in tendon.

Protein secondary structure General three-dimensional form of local segments of proteins

Protein secondary structure is the three dimensional form of local segments of proteins. The two most common secondary structural elements are alpha helices and beta sheets, though beta turns and omega loops occur as well. Secondary structure elements typically spontaneously form as an intermediate before the protein folds into its three dimensional tertiary structure.

Protein structure prediction

Protein structure prediction is the inference of the three-dimensional structure of a protein from its amino acid sequence—that is, the prediction of its secondary and tertiary structure from primary structure. Structure prediction is different from the inverse problem of protein design. Protein structure prediction is one of the most important goals pursued by computational biology; and it is important in medicine and biotechnology.

In a chain-like biological molecule, such as a protein or nucleic acid, a structural motif is a common three-dimensional structure that appears in a variety of different, evolutionarily unrelated molecules. A structural motif does not have to be associated with a sequence motif; it can be represented by different and completely unrelated sequences in different proteins or RNA.

A coiled coil is a structural motif in proteins in which 2–7 alpha-helices are coiled together like the strands of a rope. Many coiled coil-type proteins are involved in important biological functions, such as the regulation of gene expression — e.g., transcription factors. Notable examples are the oncoproteins c-Fos and c-jun, as well as the muscle protein tropomyosin.

Ramachandran plot

In biochemistry, a Ramachandran plot, originally developed in 1963 by G. N. Ramachandran, C. Ramakrishnan, and V. Sasisekharan, is a way to visualize energetically allowed regions for backbone dihedral angles ψ against φ of amino acid residues in protein structure. The figure on the left illustrates the definition of the φ and ψ backbone dihedral angles. The ω angle at the peptide bond is normally 180°, since the partial-double-bond character keeps the peptide planar. The figure in the top right shows the allowed φ,ψ backbone conformational regions from the Ramachandran et al. 1963 and 1968 hard-sphere calculations: full radius in solid outline, reduced radius in dashed, and relaxed tau (N-Cα-C) angle in dotted lines. Because dihedral angle values are circular and 0° is the same as 360°, the edges of the Ramachandran plot "wrap" right-to-left and bottom-to-top. For instance, the small strip of allowed values along the lower-left edge of the plot are a continuation of the large, extended-chain region at upper left.

Protein structure Three-dimensional arrangement of atoms in an amino acid-chain molecule

Protein structure is the three-dimensional arrangement of atoms in an amino acid-chain molecule. Proteins are polymers – specifically polypeptides – formed from sequences of amino acids, the monomers of the polymer. A single amino acid monomer may also be called a residue indicating a repeating unit of a polymer. Proteins form by amino acids undergoing condensation reactions, in which the amino acids lose one water molecule per reaction in order to attach to one another with a peptide bond. By convention, a chain under 30 amino acids is often identified as a peptide, rather than a protein. To be able to perform their biological function, proteins fold into one or more specific spatial conformations driven by a number of non-covalent interactions such as hydrogen bonding, ionic interactions, Van der Waals forces, and hydrophobic packing. To understand the functions of proteins at a molecular level, it is often necessary to determine their three-dimensional structure. This is the topic of the scientific field of structural biology, which employs techniques such as X-ray crystallography, NMR spectroscopy, cryo electron microscopy (cryo-EM) and dual polarisation interferometry to determine the structure of proteins.

Leucine zipper DNA-binding structural motif

A leucine zipper is a common three-dimensional structural motif in proteins. They were first described by Landschulz and collaborators in 1988 when they found that an enhancer binding protein had a very characteristic 30-amino acid segment and the display of these amino acid sequences on an idealized alpha helix revealed a periodic repetition of leucine residues at every seventh position over a distance covering eight helical turns. The polypeptide segments containing these periodic arrays of leucine residues were proposed to exist in an alpha-helical conformation and the leucine side chains from one alpha helix interdigitate with those from the alpha helix of a second polypeptide, facilitating dimerization.

A polyproline helix is a type of protein secondary structure which occurs in proteins comprising repeating proline residues. A left-handed polyproline II helix is formed when sequential residues all adopt (φ,ψ) backbone dihedral angles of roughly and have trans isomers of their peptide bonds. This PPII conformation is also common in proteins and polypeptides with other amino acids apart from proline. Similarly, a more compact right-handed polyproline I helix is formed when sequential residues all adopt (φ,ψ) backbone dihedral angles of roughly and have cis isomers of their peptide bonds. Of the twenty common naturally occurring amino acids, only proline is likely to adopt the cis isomer of the peptide bond, specifically the X-Pro peptide bond; steric and electronic factors heavily favor the trans isomer in most other peptide bonds. However, peptide bonds that replace proline with another N-substituted amino acid are also likely to adopt the cis isomer.

Pi helix

A pi helix is a type of secondary structure found in proteins. Discovered by crystallographer Barbara Low in 1952 and once thought to be rare, short π-helices are found in 15% of known protein structures and are believed to be an evolutionary adaptation derived by the insertion of a single amino acid into an α-helix. Because such insertions are highly destabilizing, the formation of π-helices would tend to be selected against unless it provided some functional advantage to the protein. π-helices therefore are typically found near functional sites of proteins.

3<sub>10</sub> helix Type of secondary structure

A 310 helix is a type of secondary structure found in proteins and polypeptides. Of the numerous protein secondary structures present, the 310-helix is the fourth most common type observed; following α-helices, β-sheets and reverse turns. 310-helices constitute nearly 10–15% of all helices in protein secondary structures, and are typically observed as extensions of α-helices found at either their N- or C- termini. Because of the α-helices tendency to consistently fold and unfold, it has been proposed that the 310-helix serves as an intermediary conformation of sorts, and provides insight into the initiation of α-helix folding.

Cyclol Structural model of a folded, globular protein

The cyclol hypothesis is the first structural model of a folded, globular protein. It was developed by Dorothy Wrinch in the late 1930s, and was based on three assumptions. Firstly, the hypothesis assumes that two peptide groups can be crosslinked by a cyclol reaction ; these crosslinks are covalent analogs of non-covalent hydrogen bonds between peptide groups. These reactions have been observed in the ergopeptides and other compounds. Secondly, it assumes that, under some conditions, amino acids will naturally make the maximum possible number of cyclol crosslinks, resulting in cyclol molecules and cyclol fabrics. These cyclol molecules and fabrics have never been observed. Finally, the hypothesis assumes that globular proteins have a tertiary structure corresponding to Platonic solids and semiregular polyhedra formed of cyclol fabrics with no free edges. Such "closed cyclol" molecules have not been observed either.

In polymer science, the Lifson–Roig model is a helix-coil transition model applied to the alpha helix-random coil transition of polypeptides; it is a refinement of the Zimm–Bragg model that recognizes that a polypeptide alpha helix is only stabilized by a hydrogen bond only once three consecutive residues have adopted the helical conformation. To consider three consecutive residues each with two states, the Lifson–Roig model uses a 4x4 transfer matrix instead of the 2x2 transfer matrix of the Zimm–Bragg model, which considers only two consecutive residues. However, the simple nature of the coil state allows this to be reduced to a 3x3 matrix for most applications.

Alpha sheet

Alpha sheet is an atypical secondary structure in proteins, first proposed by Linus Pauling and Robert Corey in 1951. The hydrogen bonding pattern in an alpha sheet is similar to that of a beta sheet, but the orientation of the carbonyl and amino groups in the peptide bond units is distinctive; in a single strand, all the carbonyl groups are oriented in the same direction on one side of the pleat, and all the amino groups are oriented in the same direction on the opposite side of the sheet. Thus the alpha sheet accumulates an inherent separation of electrostatic charge, with one edge of the sheet exposing negatively charged carbonyl groups and the opposite edge exposing positively charged amino groups. Unlike the alpha helix and beta sheet, the alpha sheet configuration does not require all component amino acid residues to lie within a single region of dihedral angles; instead, the alpha sheet contains residues of alternating dihedrals in the traditional right-handed (αR) and left-handed (αL) helical regions of Ramachandran space. Although the alpha sheet is only rarely observed in natural protein structures, it has been speculated to play a role in amyloid disease and it was found to be a stable form for amyloidogenic proteins in molecular dynamics simulations. Alpha sheets have also been observed in X-ray crystallography structures of designed peptides.

Schellman loop

Schellman loops are commonly occurring structural features of proteins and polypeptides. Each has six amino acid residues with two specific inter-mainchain hydrogen bonds and a characteristic main chain dihedral angle conformation. The CO group of residue i is hydrogen-bonded to the NH of residue i+5, and the CO group of residue i+1 is hydrogen-bonded to the NH of residue i+4. Residues i+1, i+2, and i+3 have negative φ (phi) angle values and the phi value of residue i+4 is positive. Schellman loops incorporate a three amino acid residue RL nest, in which three mainchain NH groups form a concavity for hydrogen bonding to carbonyl oxygens. About 2.5% of amino acids in proteins belong to Schellman loops. Two websites are available for examining small motifs in proteins, Motivated Proteins: ; or PDBeMotif:.

The Asx turn is a structural feature in proteins and polypeptides. It consists of three amino acid residues in which residue i is an aspartate (Asp) or asparagine (Asn) that forms a hydrogen bond from its sidechain CO group to the mainchain NH group of residue i+2. About 14% of Asx residues present in proteins belong to Asx turns.

Beta bend ribbon

The beta bend ribbon, or beta-bend ribbon, is a structural feature in polypeptides and proteins. The shortest possible has six amino acid residues arranged as two overlapping hydrogen bonded beta turns in which the carbonyl group of residue i is hydrogen-bonded to the NH of residue i+3 while the carbonyl group of residue i+2 is hydrogen-bonded to the NH of residue i+5. In longer ribbons, this bonding is continued in peptides of 8, 10, etc., amino acid residues. A beta bend ribbon can be regarded as an aberrant 310 helix (3/10-helix) that has lost some of its hydrogen bonds. Two websites are available to facilitate finding and examining these features in proteins: Motivated Proteins; and PDBeMotif.

ST motif

The ST motif is a commonly occurring feature in proteins and polypeptides. It consists of four or five amino acid residues with either serine or threonine as the first residue. It is defined by two internal hydrogen bonds. One is between the side chain oxygen of residue i and the main chain NH of residue i + 2 or i + 3; the other is between the main chain oxygen of residue i and the main chain NH of residue i + 3 or i + 4. Two websites are available for finding and examining ST motifs in proteins, Motivated Proteins: and PDBeMotif.

Alpha-keratin, or α-keratin, is a type of keratin found in vertebrates. This protein is the primary component in hairs, horns, mammalian claws, nails and the epidermis layer of the skin. α-keratin is a fibrous structural protein, meaning it is made up of amino acids that form a repeating secondary structure. The secondary structure of α-keratin is very similar to that of a traditional protein α-helix and forms a coiled coil. Due to its tightly wound structure, it can function as one of the strongest biological materials and has various functions in mammals, from predatory claws to hair for warmth. α-keratin is synthesized through protein biosynthesis, utilizing transcription and translation, but as the cell matures and is full of α-keratin, it dies, creating a strong non-vascular unit of keratinized tissue.

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Further reading