Introduction to Protein Secondary Structure: α-Helices and β-Sheets

Here we focus on the general aspects of protein secondary structure. Many of the discussed features are essential for practical applications − for example in sequence alignment and analysis, homology modelling and analysis of model quality, in planning mutations or in analyzing protein-ligand interactions.

The α-helix
The most common type of secondary structure in proteins is the α-helix. Linus Pauling was the first to predict the existence of α-helices. The prediction was confirmed when the first three-dimensional structure of a protein, myoglobin (by Max Perutz and John Kendrew) was determined by X-ray crystallography. An example of an α-helix is shown on the image below. This type of representation of a protein structure is called “sticks representation”. To get a better impression of how a helix looks like, only the main chain atoms of the polypeptide are shown connected by sticks, the side chains are omitted. There are 3.6 residues/turn in an α-helix, which means that there is one residue every 100 degrees of rotation (360/3.6). Each residue is translated 1.5 Å along the helix axis, which gives a vertical distance of 5.4 Å between structurally equivalent atoms in a turn (pitch of a turn). The repeating structural pattern in helices is a result of similar φ and ψ values. This is reflected in the clustering of the torsion angles within the helical region of the Ramachandran plot. In the section on the Ramachandran plot we call these regions "energetically most favourable", which means that the particular configuration of the polypeptide chain is such that main chain atoms are packed in an optimal and energetically favourable way avoiding clashes (atoms coming too close to each other).

When looking at the helix in the figure below, notice how the carbonyl (C=O) oxygen atoms (shown in red) point in one direction, towards the amide NH groups 4 residues away (i, i+4). Together these groups form a hydrogen bond, one of the main forces in the stabilization of secondary structure in proteins. The hydrogen bonds are shown as dashed lines.
The α-helix is not the only helical structure in proteins. Other helical structures include the 3_10 helix, which is stabilized by hydrogen bonds of the type (i, i+3) and the π-helix, which is stabilized by hydrogen bonds of the type (i, i+5). The 3_10 helix has a smaller radius, compared to the α-helix, while the π-helix has a larger radius. The first detailed analysis of the occurrence of the π-helix in proteins, based on the analysis of entries in the Protein Data Bank (PDB), was published by Fodje & Al-Karadaghi, 2002.
We should also note that in addition to the “simple” helical structures mentioned here, there is a number of so-called coiled-coil structures, in which two or more α-helices together build higher-order helical structures.

The β-sheet
The second major secondary structure element in proteins is the β-sheet. β-sheets consist of several β-strands, stretched segments of the polypeptide chain kept together by a network of hydrogen bonds between adjacent strands. An example of a β-sheet, with the stabilizing hydrogen bonds between adjacent strands (shown as dotted lines), is shown in the image below (left):
It is important to note that unlike in helices, in which the hydrogen bond donors and acceptors along the helix axis are separated by 4 residues, in β-sheets the hydrogen bond donors and acceptors belong to different strands and may be separated from each other by long segments of the amino acid sequence.

In the image on the right a ribbon presentation of a β-sheet is shown, this time in the context of the 3D structure to which it belongs (the coloring is according to secondary structure). Each β−strand is represented by an arrow, which defines its direction starting from the N- to the C-terminus. When the strand arrows point in the same direction, it a parallel β-sheet (the PDB code for this structure is 2OHX).

When the strand arrows point in opposite directions, we get an anti-parallel β-sheet (PDB code is 1USR, Newcastle disease virus hemagglutinin-neuraminidase), left image:
Loops, turns and hairpins
When there are only 2 anti-parallel β-strands, like in the figure on the right, it is called a β-hairpin.

A loop between the two strands is called a β-turn. Short turns and longer loops play an important role in protein 3D structures, connecting together strands to strands, strands to α-helices, or helices to helices. The amino acid sequences in loop regions are often highly variable within a protein family. But in some cases, when a loop has some specific function, for example interaction with another protein, the sequence may be conserved. Loop length in proteins from organisms living at elevated temperatures (thermophilic organisms) is usually shorter than in protein from lower-temperature family members, presumably to give a protein additional stability at high temperatures, preventing its unfolding and denaturation. During sequence alignment and homology modeling, when it is essential to have an accurate sequence alignment, the highly variable length of loop regions justifies the localization of insertions and deletions in the amino acid sequence to loop regions.

Structural motifs that contain combinations of helices, helices and strands, etc., are closely linked to protein fold. For this reason, when viewing a protein 3D structures, it is an advantage to be able to recognize the secondary structure elements and to identify structural motifs. In the next section we will examine some of the ways by which secondary structure elements connect to each other, forming common motifs and folds.