A peptide's sequence is only the start. How the chain bends, coils and folds decides what it can bind and how stable it is. Structural biologists describe this in levels.
Primary structure: the sequence
The primary structure is simply the order of amino acids from N- to C-terminus. Everything else follows from it. Change one residue and the shape and behaviour of the whole molecule can change.
Secondary structure: local patterns
The backbone of a peptide chain can form regular, repeating shapes held together by hydrogen bonds between backbone atoms.
The α-helix
Described by Linus Pauling and colleagues in 1951, the α-helix is a right-handed coil with about 3.6 residues per turn. Each backbone C=O hydrogen-bonds to the N–H four residues further along. Many peptide hormones adopt helical shapes when they bind their receptors, even if they're floppy in solution.
The β-sheet
In a β-sheet, extended stretches of chain (β-strands) line up side by side and hydrogen-bond to each other, either parallel or antiparallel. Short peptides can form β-hairpins, two strands joined by a tight turn.
Turns and loops
Turns let the chain reverse direction. Two residues have special roles. Proline's ring locks its backbone angle, so it often breaks helices and sits in turns. Glycine has no side chain, which makes it unusually flexible.
Tertiary structure and stabilising bonds
Longer peptides can fold into a compact three-dimensional shape, the tertiary structure. Several kinds of interaction hold it together:
- Disulfide bonds: covalent S–S bridges between two cysteine residues. Oxytocin and vasopressin form a ring this way, and insulin's two chains are joined by two of them.
- Hydrophobic packing: non-polar side chains cluster away from water.
- Salt bridges: attractions between oppositely charged side chains.
Why short peptides are often "disordered"
Unlike large proteins, many short peptides don't hold one fixed shape in solution. They switch rapidly between many conformations and only settle into a defined structure when they meet their binding partner. That flexibility costs binding energy, which is one reason chemists add cyclisation or staples to pre-organise the active shape.
How structure is measured
| Technique | What it reveals |
|---|---|
| Circular dichroism (CD) | Overall helix or sheet content in solution; quick and uses little sample |
| NMR spectroscopy | Atomic-level structure and flexibility in solution |
| X-ray crystallography | High-resolution structure, if the peptide or complex can be crystallised |
| Cryo-electron microscopy | Structures of peptides bound to large receptors |
| Computational prediction | AI models such as AlphaFold predict structures from sequence |
Key takeaway: sequence decides shape, and shape decides function. Much of peptide design is the art of controlling shape.
Related articles
- A brief history of peptide science
- How peptide receptors work: GPCRs explained
- Peptides in nature: the body's messengers
Sources and further reading
- Pauling L, Corey RB, Branson HR. The structure of proteins: two hydrogen-bonded helical configurations of the polypeptide chain. PNAS 1951;37:205–211. doi:10.1073/pnas.37.4.205 · PMID: 14816373
- Jumper J et al. Highly accurate protein structure prediction with AlphaFold. Nature 2021;596:583–589. doi:10.1038/s41586-021-03819-2 · PMID: 34265844
- Craik DJ, Fairlie DP, Liras S, Price D. The future of peptide-based drugs. Chem Biol Drug Des 2013;81:136–147. doi:10.1111/cbdd.12055 · PMID: 23253135