Unlike proteins with stable tertiary folds, peptide secondary structures are dynamic and often induced by interaction with targets.
Secondary Structure in Peptides vs. Proteins
Proteins - **Stable** — Locked by tertiary contacts - **Fixed** — Consistent across conditions - **Cooperative** — Elements reinforce each other
Peptides - **Dynamic** — Fluctuate between conformations - **Ensemble** — Population of structures - **Induced** — Often form only upon binding
Major Secondary Structure Motifs
α-Helix - 3.6 residues per turn - i→i+4 hydrogen bonds - Rise of 1.5 Å per residue
- Often transient in solution
- Stabilized by membrane contact
- Can be locked by stapling
3₁₀-Helix - Tighter than α-helix (3 residues/turn) - i→i+3 hydrogen bonds - More common in short peptides - Often at helix termini
β-Turns - Tight reversal of chain direction - 4 residues - Important for: - Chain direction changes - Recognition epitopes - Cyclic peptide geometry
- Type I, II, III (most common)
- Distinguished by φ,ψ angles
β-Hairpin - Two antiparallel β-strands - Connected by turn - Requires ~8+ residues for stability - Common in cyclic peptides
Polyproline II (PPII) Helix - Left-handed helix - Extended conformation - No internal hydrogen bonds - **Major component of "random coil"**
The "Random Coil" Myth
- Ensemble of structures
- PPII helix predominates
- Fluctuating local structure
- Not truly random
Induced Folding
Many bioactive peptides are disordered in solution but fold upon:
1. Membrane Interaction **Example: LL-37 (cathelicidin)** - Random coil in aqueous solution - Forms amphipathic α-helix at membrane - Insertion requires folded state
2. Receptor Binding **Example: Neuropeptide Y** - Flexible in solution - Structured upon GPCR binding - Receptor provides folding template
3. Metal Binding **Example: Zinc finger peptides** - Disordered without metal - Structured upon Zn²⁺ coordination
Engineering Stable Secondary Structure
Peptide Stapling - Hydrocarbon cross-links - Lock α-helical structure - Positions i, i+4 or i, i+7 - **Example: ALRN-6924**
Cyclization - Head-to-tail - Disulfide bridges - Lactam bridges - Reduces conformational entropy
Helix Caps - N-cap: Asp, Asn, Ser (H-bond acceptors) - C-cap: Gly, Asn (special geometry) - Stabilize helix termini
Non-Natural Amino Acids - Aib (α-aminoisobutyric acid) — Promotes helix - D-amino acids — Create specific turns - Proline analogs — Control conformation
Therapeutic Implications
| Strategy | Effect | Example Drug |
|---|---|---|
| Stapling | Lock α-helix | ALRN-6924 |
| Cyclization | Constrain backbone | Cyclosporin A |
| D-amino acids | Stabilize turns | Semaglutide |
| N-methylation | Reduce flexibility | Cyclosporin A |