Secondary Structure: Helices and Sheets
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You should recall the 20 standard amino acids, the peptide bond, and the concept that the primary structure (amino-acid sequence) dictates higher-order folding. Familiarity with hydrogen bonding is essential, as it is the primary force stabilising secondary structures.
Why this matters
Secondary structure is the first level of local order in a polypeptide chain, driven by backbone hydrogen bonding.
While the primary structure defines the linear sequence of amino acids, secondary structure describes the regular, repeating local conformations adopted by the polypeptide backbone. These structures, primarily the \(\alpha\)-helix and the \(\beta\)-sheet, are stabilised by hydrogen bonds between the carbonyl oxygen (\(C=O\)) and the amide hydrogen (\(N-H\)) of the peptide backbone. Understanding these motifs is crucial because they form the building blocks of the tertiary structure, influencing protein stability, flexibility, and function. The specific geometry of these structures is determined by the steric constraints of the peptide bond and the side chains, as described by the Ramachandran plot.
The Backbone Constraints
The polypeptide backbone is not a freely rotating chain. The peptide bond itself is planar and rigid due to partial double-bond character, restricting rotation around the \(C-N\) bond. This leaves two rotatable bonds per residue: rotation about the N–C\(\alpha\) bond, measured by the angle \(\phi\), and rotation about the C\(\alpha\)–C′ bond, measured by \(\psi\). The combination of these two angles determines the local conformation of the backbone. Steric clashes between atoms, particularly the side chains and the backbone atoms, restrict the allowed combinations of \(\phi\) and \(\psi\). The Ramachandran plot maps these allowed regions. The \(\alpha\)-helix and \(\beta\)-sheet correspond to specific, energetically favourable regions on this plot where hydrogen bonding is optimised and steric clashes are minimised. Almost any sequence can adopt these conformations, though residues differ in their propensities; proline, with its rigid ring and no amide hydrogen, disrupts them.
The \(\alpha\)-Helix
The \(\alpha\)-helix is a right-handed spiral structure. In this conformation, the backbone hydrogen bonds form between the carbonyl oxygen of residue \(i\) and the amide hydrogen of residue \(i+4\). This creates a stable, rod-like structure. The helix has 3.6 residues per turn and a rise of 1.5 \(\mathrm{\AA}\) per residue, resulting in a pitch of 5.4 \(\mathrm{\AA}\) per turn. The side chains project outward from the helical axis, allowing them to interact with the solvent or other parts of the protein. The \(\alpha\)-helix is common in globular proteins and is stabilised by the intrachain hydrogen bonds. The geometry of the helix is such that the dipole moments of the peptide bonds align, creating a significant net dipole moment along the helix axis, which can influence the electrostatic environment of the protein.
The \(\beta\)-Sheet
The \(\beta\)-sheet consists of extended polypeptide strands aligned side-by-side. Adjacent strands are stabilised by inter-strand hydrogen bonds between the carbonyl oxygen of one strand and the amide hydrogen of the neighbouring strand. The strands can be parallel (running in the same \(N\)-to-\(C\) direction) or antiparallel (running in opposite directions). In antiparallel sheets, the hydrogen bonds are linear and stronger, while in parallel sheets, the bonds are slightly angled. The side chains alternate above and below the plane of the sheet. \(\beta\)-sheets are often found in fibrous proteins and contribute to the structural rigidity of proteins. The stability of the sheet depends on the number of hydrogen bonds and the packing of the side chains. Misfolding of \(\beta\)-sheets is associated with amyloid diseases, where sheets aggregate into insoluble fibrils.
Coil and Turn Regions
Not all regions of a protein adopt regular secondary structures. Coil regions, also known as random coils, lack a specific repeating pattern. These regions are often found on the surface of proteins and are flexible, allowing for conformational changes. Turns, such as \(\beta\)-turns, are short sequences of four residues that reverse the direction of the polypeptide chain. They are stabilised by hydrogen bonds between the first and fourth residues. Turns are crucial for compacting the protein structure and connecting secondary structure elements. The presence of glycine and proline in turns is common due to their unique conformational flexibility and steric properties. These non-regular structures are essential for the overall three-dimensional fold and function of the protein.
The concept
The levels of protein structure
From amino-acid sequence to folded, functional shape.
A common misconception is that secondary structure is determined solely by the amino-acid sequence. While the sequence dictates the propensity for certain structures, the local environment, including solvent conditions and interactions with other parts of the protein, also plays a significant role. For instance, a sequence that favours an \(\alpha\)-helix in isolation may form a \(\beta\)-sheet in the context of a larger protein due to steric constraints or hydrogen bonding partners. Additionally, the distinction between "random coil" and "disordered" regions is subtle; disordered regions may adopt transient secondary structures that are critical for function. C
Worked example
Problem. A polypeptide chain contains a segment of 18 residues that forms a perfect \(\alpha\)-helix. Calculate the total length of this helical segment along its axis. Assume the rise per residue is 1.5 \(\mathrm{\AA}\).
- Identify the number of residues in the helix: \(n = 18\).
- Identify the rise per residue: \(h = 1.5\ \mathrm{\AA}\).
- Calculate the total length \(L\) by multiplying the number of residues by the rise per residue: \(L = n \times h\).
- Substitute the values: \(L = 18 \times 1.5\ \mathrm{\AA}\).
- Perform the multiplication: \(L = 27\ \mathrm{\AA}\).
Units check. The number of residues is dimensionless, and the rise per residue is in \(\mathrm{\AA}\), so the result is in \(\mathrm{\AA}\), which is consistent with length.
Three quick tests
- What is the primary stabilising force for the \(\alpha\)-helix?
Answer
Hydrogen bonds between the backbone carbonyl oxygen and amide hydrogen, specifically between residue \(i\) and \(i+4\). - How many residues are there per turn in a standard \(\alpha\)-helix?
Answer
3.6 residues per turn. - In an antiparallel \(\beta\)-sheet, how are the hydrogen bonds oriented?
Answer
The hydrogen bonds are linear and perpendicular to the strand direction, resulting in stronger bonds compared to parallel sheets.
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Lecture notes drafted with a local model and checked line by line by the editor; every number in the worked example was recomputed.