Secondary structure of protein in biochemistry

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Secondary Structure of Proteins

The secondary structure of a protein refers to recurring, localized structural patterns that form within short regions of a polypeptide chain. These structures arise when atoms of the peptide backbone form regular hydrogen bonds - they represent the second level of protein organization, sitting between the primary (linear amino acid sequence) and the tertiary (overall 3D fold) levels.

Four levels of protein structure - primary, secondary, tertiary, and quaternary

Fig. 2.1 - The four hierarchies of protein structure (Lippincott Biochemistry, 8th ed.)

Basis: The Peptide Backbone

Before secondary structure can form, there are geometric constraints on the polypeptide backbone. The peptide bond itself has partial double-bond character due to resonance, which keeps the carbonyl C and the amide N in the same plane (a rigid planar unit). Rotation is only allowed around the bonds connecting each alpha-carbon (Cα) to its neighboring atoms - described by torsion angles phi (φ) and psi (ψ). Steric clashes between side chains restrict which angles are permissible, which in turn limits the secondary structures that can form.

Biochemistry, Lippincott 8th ed., p. 51
Basic Medical Biochemistry - A Clinical Approach, 6e, p. 181

The Two Major Regular Secondary Structures

1. The α-Helix

The alpha helix showing intrachain hydrogen bonds parallel to the backbone and side chains projecting outward

Fig. 2.6 - Structure of an α-helix (Lippincott Biochemistry, 8th ed.)

The α-helix is the most common secondary structure element. Key features:

Property	Detail
Shape	Right-handed spiral (clockwise when viewed from N to C terminus)
Amino acids per turn	3.6 residues per full turn
Hydrogen bonds	Each C=O (carbonyl oxygen) of one peptide bond forms an H-bond with the N-H of the residue 4 positions ahead in the chain
H-bond orientation	Parallel to the helix axis (backbone)
Side chains	Project outward and backward from the central axis, avoiding steric clash
Stabilization	All peptide bonds (except first and last) are involved in H-bonding

The α-helix is found in diverse proteins: the near-entirely helical keratins (hair, skin, nails) and globular proteins like myoglobin.

Amphipathic helices: The arrangement of R groups can create a helix with one polar face and one nonpolar face - important for membrane-spanning and lipid-interacting proteins.

Amino acids that disrupt the α-helix:

Proline - its rigid secondary amino group (the N is part of a ring) cannot adopt the required geometry; it inserts a kink and is called a "helix breaker"
Glycine - too much conformational flexibility
Amino acids with bulky R groups (e.g., tryptophan), charged R groups (e.g., glutamate), or β-carbon branching (e.g., valine) are disfavored
Lippincott Biochemistry, 8th ed., p. 60-62
Basic Medical Biochemistry, 6e, p. 182

2. The β-Sheet (β-Pleated Sheet)

The β-sheet is the second major regular secondary structure. All peptide bond components participate in hydrogen bonding.

Key features:

Formed by two or more polypeptide strands (β-strands) aligned laterally
Stabilized by H-bonds between C=O and N-H groups of adjacent strands - these bonds are perpendicular to the polypeptide backbone (contrast with the α-helix where they are parallel)
The surface has a pleated (corrugated) appearance because successive α-carbons lie slightly above and below the plane of the sheet
β-strands are almost fully extended (much more extended than in the helix)
The sheet has a right-handed curl (twist) when viewed along the backbone
R groups of adjacent residues project alternately above and below the plane of the sheet

Two types of β-sheets:

Type	Description
Antiparallel	Adjacent strands run in opposite directions (alternating N-termini); H-bonds are more linear (stronger)
Parallel	Adjacent strands run in the same direction; H-bonds are slightly distorted

Just as with the α-helix, the positioning of R groups can make β-sheets amphipathic (with polar and nonpolar faces).

Lippincott Biochemistry, 8th ed., p. 63-64

Non-Regular Secondary Structures

3. β-Bends (β-Turns / Reverse Turns)

Allow the polypeptide chain to reverse direction, giving proteins their compact globular shape
Usually found on the surface of proteins, often containing charged residues
Connect successive strands of antiparallel β-sheets
Typically composed of 4 amino acids
Common residues: Proline (causes kink) and Glycine (smallest R group, allows tight turns)
Stabilized by an H-bond between the C=O of residue 1 and the N-H of residue 4

4. Loops and Coils

About half of an average globular protein is organized into repetitive (regular) structures (α-helices and β-sheets). The rest consists of loops and coils - segments that connect helices and sheets.

Important points:

These are NOT random - they have specific, reproducible conformations stabilized by H-bonds dictated by the primary sequence
They should never be called "random coils" (that term is reserved for denatured proteins)
They are generally more flexible than helices or β-sheets
They often form hinge regions that allow protein segments to move during ligand binding or folding
Named loops include Ω-loops (omega loops)
Lippincott Biochemistry, 8th ed., p. 65
Basic Medical Biochemistry, 6e, p. 187

Summary Comparison Table

Feature	α-Helix	β-Sheet	β-Bend
Shape	Right-handed coil	Extended, pleated strands	4-residue hairpin turn
H-bond direction	Parallel to helix axis	Perpendicular to strand	Between residues 1 and 4
H-bond linkage	i to i+4 within one chain	Between separate strands	Within the turn
Side chain orientation	Outward from helix	Alternate above/below plane	Variable
Helix breaker	Proline, Gly, bulky/branched R groups	-	Pro, Gly common
Strand orientation	-	Parallel or antiparallel	-
Example proteins	Keratin, myoglobin	Silk fibroin, IgG	Connecting loops

Stabilizing Forces in Secondary (and Higher) Structure

Secondary structure is maintained primarily by hydrogen bonds between backbone atoms. Overall protein conformation (tertiary/quaternary) is further stabilized by:

Disulfide bonds (-S-S-) between cysteine residues (covalent)
Hydrophobic interactions - nonpolar side chains cluster in the interior
Ionic interactions - between oppositely charged R groups
Van der Waals forces - nonspecific close-range attractions
Hydrogen bonds involving side chains

Lippincott Biochemistry, 8th ed., p. 70-72
Basic Medical Biochemistry, 6e, p. 188

Clinical Relevance

Alterations in secondary/tertiary structure have major clinical consequences:

Prion diseases (Creutzfeldt-Jakob disease, scrapie): normal PrP^C protein (predominantly α-helical) misfolds into PrP^Sc (predominantly β-sheet), which is protease-resistant and aggregates - causing neurodegeneration
Sickle cell disease: a single amino acid substitution (Val for Glu at position 6 of β-globin) leads to abnormal hydrophobic interactions and polymerization under low oxygen conditions
Amyloid diseases (Alzheimer's, type 2 diabetes): normally soluble proteins misfold into β-sheet-rich fibrils that deposit in tissues

Sources: Biochemistry, Lippincott Illustrated Reviews, 8th ed. | Basic Medical Biochemistry - A Clinical Approach, 6th ed.

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