Peptide Bond

The peptide bond is an amide link created when the carboxyl group of one amino acid condenses with the amino group of the following one, giving off a water molecule. It forms the covalent backbone of all peptides, and its physical characteristics account for much of what peptide chemists have to design around.

Geometry and stability

Through resonance, the C–N bond takes on partial double-bond character, which keeps the amide unit flat and restricts rotation around it; the backbone’s conformational freedom sits instead in the neighbouring phi and psi angles. This flatness is why chains fold into predictable helices and turns. Thermodynamically the bond favours hydrolysis, but kinetically the reaction is extremely slow — without a catalyst, half-lives at neutral pH run to centuries — so in biological fluids it is proteases, not water, that actually break peptides down.

Protecting the backbone

All approaches to prolonging peptide half-life act on this backbone or next to it: swapping in D-amino acids, inserting Aib, acetylating the N-terminus, amidating the C-terminus, or adding a fatty acid so the peptide binds albumin. During manufacturing, making one such bond is the recurring cycle of solid-phase peptide synthesis; if a coupling is incomplete at any position, deletion sequences result, visible as shoulder peaks in HPLC and as missing mass in MS.

Related terms

amino acid · degradation · disulfide bridge. Further reading: peptide stability and half-life.