Lecture 10 Summary

The conformational space of a polypeptide chain can be represented as an ordered set of points on a Ramachandran plot. Locally repeating patterns of main-chain dihedral angles give rise to what we call secondary structure - principally involving α-helix and β-strand conformations - correspond to clusters of points on a Ramachandran plot.

The α helix

The α-helix (alpha helix) is a fundamental motif of protein structure. In the hierarchy of protein structure, the α-helix - as a locally regular or repetitive conformation of the polypeptide chain - is a type of secondary structure. It is formed by the coiling of the polypeptide chain such that the carbonyl oxygen atom at residue n forms a hydrogen bond with the amide group of residue n + 4. The ideal α-helix has 3.6 residues per turn and a rise per residue of 1.5 Å. ( "Å" = "angstrom", 1 Å = 1 × 10⁻¹⁰ m) The phi (φ) and psi (ψ) angles for this ideal geometry are −57°, −47°. At right is shown a "stick" representation of an ideal α-helix made up of 16 amino acids (without side chains) linked in a short polypeptide, with the N terminus at the bottom. The hydrogen bonds are indicated by the dashed yellow lines. Hydrogen bond distances range from about 1.8 to 1.9 Å between the oxygen and hydrogen atoms.

A helix can be defined geometrically as a three-dimensional curve having an axis, width or diameter, and a pitch. Note how these hydrogen bonds, which maintain the conformation (or "shape") of the chain, are all roughly aligned along the helix axis. Given what was said above about the geometry of an ideal α-helix, the 16-residue segment shown here is about 24 Å or 240 nm long, and we should expect to see about five turns of the helix.

Another feature of the α-helix is its handedness or chirality. The helices in naturally-occurring proteins are all right-handed. A right-handed α-helix is non-superimposible on its mirror image, in the same way you cannot superimpose your right and left hands.

β-strands and sheets

Along with the α-helix, the β-strand is another fundamental element of protein secondary structure. The polypeptide chain in a β-strand is close to being fully extended, which would correspond to φ = ψ = 180°. The β-strand is a regularly repeating main chain conformation, just like the α-helix. In fact, it can be thought of as a helix with approximately 180°/residue twist (~2 residues/turn) and a translation per residue of 3.5 Å. Two β-strands can be aligned side-by-side to form favorable interactions between strands via H-bonds between the main chain amide and carbonyl groups. The alignment of strands may be parallel or antiparallel. A number of such aligned strands form structures in proteins known as β-sheets. If the adjacent strands are all aligned in an antiparallel fashion, the sheet is an antiparallel β-sheet. If adjacent strands are parallel, the sheet formed is said to be a parallel β-sheet. β-sheets in which some adjacent strands are parallel, while others are antiparallel are termed mixed β-sheets. The β-sheets observed in proteins all show varying degrees of twist - that is, the sheets are never perfectly "flat".

Connecting 2° structure elements: Turns

The architecture of globular proteins tends to be characterized by secondary structural elements that crisscross or traverse the molecule, and connecting segments where the direction of the polypeptide chain reverses, and the next 2° structure segment leads back toward the center of the molecule. These connecting segments - short turns and longer loops - thus tend to occur at the surface of the globular protein. Often such turn or loop segments are quite important for the protein's function.

The figure at right illustrates two simple ways in which β-strand elements can be connected. This more abstract way of representing protein structural features is called a topology diagram. Note that the β-hairpin motif aligns the connected β-strands in an antiparallel orientation, whereas an α-helix (or an extended loop) can be used to connect β-strands in a parallel fashion, by forming a β-α-β motif.

"Helical wheel" diagram and amphipathic helices

The figure shows the positions of the side chains along a regular α-helix. For a right-handed helix with 3.6 residues per turn, rotation is clockwise as the polypeptide chain is followed N to C, and the 5th residue ends up in a position 40° clockwise relative to residue 1. Note that over a number of turns of the helix (21 residues or nearly six turns of the helix), a pattern of distribution of the side chains emerges in this example. Nonpolar side chains group on one side of the helix, whereas polar and charged side chains are grouped to the other side. This gives the helix an amphipathic character, having obvious implications for the orientation of such a helix in the context of tertiary structure. The nonpolar face of the helix will interact favorably with (or form part of) the hydrophobic core of a globular protein, while the hydrophilic face will orient toward the surface.

The helical wheel diagram for a coiled-coil motif

As has been mentioned, α-helices interact with other elements of protein structure mainly through side chain contacts. A further example of this is the coiled coil motif, which occurs in many structural proteins such as keratin, and an important class of transcription factors known as bZIP transcription factors. If an α-helix is slightly distorted so that it has 3.5 residues per turn, then every seventh side chain will emanate from the same angular position on the helix surface (translated, of course, parallel to the helix axis, by 10 Å or so). This is known as a heptad repeat, and the energy required to distort the helix from the ideal geometry is made up for by favorable interactions between side chains in two or more such helices.

Structure determination: Tertiary and higher structures are obtained experimentally by X-ray crystallography and multidimensional nuclear magnetic resonance (NMR).

Fibrous proteins: Keratin and the collagen triple helix.

Learning objectives

• Define and describe the features of the α helix conformation.
• Describe the molecular surface features characteristic of α helices and interactions between them.
• Define and describe the features of the β-strand conformation.
• Describe the molecular surface features characteristic of β strands and how interactions between them form β sheets in proteins.

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References

1. Branden, Carl & Tooze, John Introduction to Protein Structure (1st ed. 1991, Garland Publishing)
2. Creighton, TE. Proteins: Structure and Molecular Properties (2nd ed, 1993. Freeman)
3. Harbury PB, Zhang T, Kim PS, Alber T. "A switch between two-, three-, and four-stranded coiled-coils in GCN4 leucine zipper mutants" (1993) Science 262: 1401-1407.
4. Schulz GE, Schirmer RH. Principles of Protein Structure (1979, Springer-Verlag)