Short answer: The alpha helix (α-helix) is a right-handed coil of the polypeptide backbone, held together by hydrogen bonds between each backbone N–H and the C=O of the residue four positions earlier [1][3]. It has 3.6 residues per turn and a pitch of 5.4 Å [1]. Alanine has the highest helix propensity, glycine the lowest apart from proline [5]. A rapid lab check for helix content is circular dichroism, where an α-helix gives negative bands at 222 and 208 nm [9].
This article is educational chemistry for laboratory readers. It does not describe effects in people or animals and is not guidance for human or animal use.
What an alpha helix is
Secondary structure is the local folding of a polypeptide chain. The two most common types are the α-helix and the β-pleated sheet, and both are held in shape by hydrogen bonds [2]. (For how secondary structure fits between sequence and the overall fold, see our peptide vs protein guide.)
In an α-helix the backbone coils like a spiral staircase [1]:
- Handedness: right-handed [1].
- Residues per turn: 3.6 [1][2].
- Pitch (distance between coils): 540 pm, or 5.4 Å [1]. Dividing 5.4 Å by 3.6 residues gives about 1.5 Å of rise per residue, and 360° ÷ 3.6 gives a twist of 100° per residue.
- Side chains: the R groups point outward from the helix [2].
- Hydrogen-bond length: an N–H···O distance of 2.8 Å [1].
The hydrogen-bond pattern: i to i−4
The helix is stabilized by hydrogen bonds between amide N–H groups and C=O groups four residues away [1]. IUPAC-IUB conformation nomenclature states it precisely: the N–H of residue i is hydrogen bonded to the O=C of residue i−4, so the α-helix has "i to (i−4)", or (5→1), hydrogen bonding [3].
The same recommendations give a second name. A helix can be labelled with the number of residues per turn, followed by a subscript giving the number of atoms in the ring closed by one hydrogen bond. In that notation the α-helix is a 3.6₁₃ helix [3].
A helical conformation also tucks the amide bonds inside the coil [11]. (For the chemistry of the amide link, see our peptide bond guide.)
Phi and psi angles
Backbone shape is described by two torsion angles per residue, φ (rotation about N–Cα) and ψ (rotation about Cα–C′) [4]. IUPAC-IUB tabulates approximate values for regular structures [4]:
- Right-handed α-helix (α-poly(L-alanine)): φ −57°, ψ −47°, ω +180°.
- Left-handed α-helix: φ +57°, ψ +47°.
- Antiparallel pleated sheet (β-poly(L-alanine)): φ −139°, ψ +135°.
- Parallel pleated sheet: φ −119°, ψ +113°.
Real helices are not ideal. In a survey of 57 protein crystal structures, Barlow and Thornton found 291 α-helices, 71 3₁₀-helices and no π-helices. The mean φ, ψ angles were (−62°, −41°) for α-helices and (−71°, −18°) for 3₁₀-helices [7]. Of 48 α-helices analysed at high resolution, only 15% were linear. 58% were curved and 17% were kinked [7].
Which amino acids favour a helix?
Helix propensity is the tendency of some amino acids to occur in α-helices more often than others [5]. Pace and Scholtz built a scale from 11 experimental systems, covering both proteins and peptides, for solvent-exposed residues in the middle of a helix [5]. Values are the free-energy cost relative to alanine, in kcal/mol, so smaller numbers mean a stronger helix former [5]:
- Ala: 0 (highest propensity)
- Leu: 0.21; Arg: 0.21; Met: 0.24; Lys: 0.26
- Gln: 0.39; Glu: 0.40; Ile: 0.41; Trp: 0.49; Ser: 0.50
- Tyr: 0.53; Phe: 0.54; Val: 0.61; His: 0.61; Asn: 0.65
- Thr: 0.66; Cys: 0.68; Asp: 0.69
- Gly: 1 (lowest, excluding proline)
The same paper reports that the average globular protein contains 30% α-helix, the most common type of secondary structure [5].
Can a short peptide form a helix on its own?
The classical view was that the α-helix is only marginally stable in water and that short helices are unstable [8]. Marqusee, Baldwin and colleagues at Stanford challenged that:
- Alanine-based 16-mers: short, 16-residue alanine-based peptides showed stable α-helix formation in H₂O. The authors concluded the likely explanation was that individual alanine residues have a high helical potential [8].
- Salt-bridge spacing: in designed peptides 16 or 17 residues long with blocked ends and three Glu/Lys pairs, pairs spaced i, i+4 gave more helix than pairs spaced i, i+3. The best design reached about 80% helicity in 0.01 M NaCl at pH 7 and 0 °C [10].
- Helix dipole: swapping the positions of Glu and Lys usually changed stability in the way expected for charged groups interacting with the helix dipole [10].
Locking a helix: stapled peptides
One way chemists hold a short peptide in a helical shape is to link the side chains of two amino acids, which gives a "stapled" peptide [11] (see our cyclic peptides guide):
- Spacing: the linked residues are usually at positions i and i+4 (or i+3), or i and i+7 [11].
- Brace length: i, i+4 staples generally use 7–8 atom chains. i, i+7 staples use 10–12 atom chains, in many cases with a D-amino acid at one side of the brace [11]. (See our D-amino acids guide.)
- Chemistry: one route is ring-closing metathesis (RCM). The double bond it leaves can then be reduced to give a fully saturated bridge [11].
- Protease resistance in vitro: the review explains that proteases need peptides in an extended conformation to hydrolyse amide bonds. A helix hides those bonds inside the coil, and a staple also blocks chymotrypsin cleavage at sites between or right next to the stapled residues [11].
How labs measure helicity
Circular dichroism (CD) is, in Greenfield's words, an excellent method for rapidly evaluating secondary structure [9]. Different secondary structures give characteristic CD spectra [9]:
- α-helix: negative bands at 222 nm and 208 nm and a positive band at 193 nm [9].
- Antiparallel β-sheet: a negative band at 218 nm and a positive band at 195 nm [9].
- Disordered: very low ellipticity above 210 nm and negative bands near 195 nm [9].
Solvent matters. Trifluoroethanol (TFE) and other alcohol cosolvents have been used for decades to denature proteins and to stabilize structures in peptides [13]. Greenfield notes that TFE and hexafluoropropanol are transparent down to 185 nm but will change the structure of proteins and polypeptides [9]. So a helix seen in TFE does not by itself show that the same peptide is helical in water. (TFE is a different compound from trifluoroacetic acid, the counterion covered in our TFA guide.)
Frequently Asked Questions
What is an alpha helix in simple terms?
A right-handed coil of a protein or peptide backbone, held by hydrogen bonds between N–H and C=O groups four residues apart [1].
How many amino acids are in one turn of an alpha helix?
3.6 residues per turn [1][2].
What is the pitch of an alpha helix?
5.4 Å (540 pm) per turn [1].
Which amino acids are weakest at forming a helix?
Glycine has the lowest helix propensity on the Pace–Scholtz scale, about 1 kcal/mol less favourable than alanine, and proline was excluded from the scale [5]. Where proline kinks a helix in proteins, the kink is about 26° [7].
What is the difference between an alpha helix and a 3₁₀ helix?
They have different backbone angles: about (−62°, −41°) for α-helices and (−71°, −18°) for 3₁₀-helices in protein structures [7]. In that survey α-helices were about four times as common (291 vs 71) [7].
How do you tell if a peptide is helical?
Circular dichroism: an α-helix shows negative bands at 222 and 208 nm and a positive band at 193 nm [9].
Bottom line
The α-helix is a right-handed backbone coil with 3.6 residues per turn and a 5.4 Å pitch, held by i→i−4 backbone hydrogen bonds [1][3]. Its ideal angles are near φ −57°, ψ −47° [4]. Alanine is the strongest helix former, glycine the weakest apart from proline, and proline can kink helices [5][7]. Short peptides can be helical in water when the sequence is designed for it [8][10], side-chain staples can lock the shape [11], and CD at 222/208 nm gives a rapid way to check it [9].
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