Apolyproline helix is a type ofproteinsecondary structure which occurs in proteins comprising repeatingproline residues.[1] A left-handedpolyproline II helix (PPII,poly-Pro II, κ-helix[2]) is formed when sequential residues all adopt (φ,ψ) backbonedihedral angles of roughly (-75°, 150°) and havetrans isomers of theirpeptide bonds. This PPII conformation is also common in proteins and polypeptides with other amino acids apart from proline. Similarly, a more compact right-handedpolyproline I helix (PPI,poly-Pro I) is formed when sequential residues all adopt (φ,ψ) backbonedihedral angles of roughly (-75°, 160°) and havecis isomers of theirpeptide bonds. Of the twenty common naturally occurringamino acids, onlyproline is likely to adopt thecis isomer of thepeptide bond, specifically the X-Pro peptide bond; steric and electronic factors heavily favor thetrans isomer in most other peptide bonds. However,peptide bonds that replaceproline with anotherN-substituted amino acid (such assarcosine) are also likely to adopt thecis isomer.
The PPII helix is defined by (φ,ψ) backbonedihedral angles of roughly (-75°, 150°) andtrans isomers of thepeptide bonds. The rotation angle Ω per residue of any polypeptide helix withtrans isomers is given by the equation
Substitution of the poly-Pro II (φ,ψ) dihedral angles into this equation yields almost exactly Ω = -120°, i.e., the PPII helix is a left-handed helix (since Ω is negative) with three residues per turn (360°/120° = 3). The rise per residue is approximately 3.1 Å. This structure is somewhat similar to that adopted in the fibrous proteincollagen, which is composed mainly of proline,hydroxyproline, andglycine. PPII helices are specifically bound bySH3 domains; this binding is important for manyprotein-protein interactions and even for interactions between the domains of a single protein.
The PPII helix is relatively open and has no internalhydrogen bonding, as opposed to the more common helicalsecondary structures, thealpha helix and its relatives the310 helix and thepi helix, as well as theβ-helix. The amide nitrogen and oxygen atoms are too far apart (approximately 3.8 Å) and oriented incorrectly for hydrogen bonding. Moreover, these atoms are both H-bondacceptors in proline; there is no H-bond donor due to the cyclic side chain.
The PPII backbone dihedral angles (-75°, 150°) are observed frequently in proteins, even for amino acids other thanproline.[3] TheRamachandran plot is highly populated in the PPII region, comparably to thebeta sheet region around (-135°, 135°). For example, the PPII backbone dihedral angles are often observed inturns, most commonly in the first residue of a type II β-turn. The "mirror image" PPII backbone dihedral angles (75°, -150°) are rarely seen, except in polymers of theachiral amino acidglycine. The analog of the poly-Pro II helix in poly-glycine is called thepoly-Gly II helix. Some proteins, such as the antifreeze protein ofHypogastrura harveyi consist of bundles of glycine-rich polyglycine II helices.[4] This remarkable protein, whose 3D structure is known,[5] has unique NMR spectra and is stabilized by dimerization and 28 Cα-H··O=C hydrogen bonds.[6] The PPII helix is not common intransmembrane proteins, and this secondary structure does not traverselipid membranes in natural conditions. In 2018, a group of researchers from Germany experimentally observed the first transmembrane PPII helix formed by specifically designedartificial peptides.[7][8]
The poly-Pro I helix is much denser than the PPII helix due to thecis isomers of itspeptide bonds. It is also rarer than the PPII conformation because thecis isomer is higher in energy than thetrans. Its typical dihedral angles (-75°, 160°) are close, but not identical to, those of the PPII helix. However, the PPI helix is aright-handed helix and more tightly wound, with roughly 3.3 residues per turn (rather than 3). The rise per residue in the PPI helix is also much smaller, roughly 1.9 Å. Again, there is no internal hydrogen bonding in the poly-Pro I helix, both because an H-bond donor atom is lacking and because the amide nitrogen and oxygen atoms are too distant (roughly 3.8 Å again) and oriented incorrectly.
Traditionally, PPII has been considered to be relatively rigid and used as a "molecular ruler" in structural biology, e.g., to calibrateFRET efficiency measurements. However, subsequent experimental and theoretical studies have called into question this picture of a polyproline peptide as a "rigid rod".[9][10] Further studies using terahertz spectroscopy and density functional theory calculations highlighted that polyproline is in fact much less rigid than originally thought.[11] Interconversions between the PPII and PPI helix forms of poly-proline are slow, due to the high activation energy of X-Procis-trans isomerization (Ea ≈ 20 kcal/mol); however, this interconversion may be catalyzed by specific isomerases known asprolyl isomerases or PPIases. The interconversion between the PPII and PPI helices involve thecis-trans peptide bond isomerization along the whole peptide chain. Studies based onion-mobility spectrometry revealed existence of a defined set of intermediates along this process.[12]
| Curves |  | ||
|---|---|---|---|
| Helices |
| ||
| Spirals | |||