What are peptides?

Every amino acid carries two groups on the same carbon atom, the alpha carbon: an amino group (−NH₂; in proline, an −NH− closed into a ring) and a carboxylic acid group (−COOH). A third attachment, the side chain, is what makes one amino acid different from the next. In glycine the side chain is a single hydrogen atom. In lysine it is a chain of four carbons ending in a second amino group.

The proteins of living things are built from 20 standard amino acids. Each has a three-letter and a one-letter code: glycine is Gly or G, lysine is Lys or K. Amino acid codes lists all twenty with their formulas and masses.

Every standard amino acid except glycine exists in two mirror-image forms, L and D. Proteins are made from the L forms. A synthetic peptide sometimes contains a D amino acid on purpose, and its name then says so.

When the acid group of one amino acid reacts with the amino group of another, the two join and release one molecule of water. The new link is an amide bond; between amino acids it is called a peptide bond. Each further reaction adds one unit to the chain and releases one more water.

Two facts about the bond matter in practice:

• It is flat and rigid. It has partial double-bond character, so the atoms around it sit in one plane and do not turn freely. That rigidity shapes the way chains fold.
• Water can break it. Hydrolysis reverses the reaction and returns the two amino acids. In neutral water at room temperature it is slow; heat, acids, bases and enzymes speed it up. This is one reason a peptide keeps far longer as a dry powder than in solution.

Because each link costs a water molecule, the units inside a chain are called residues. A residue weighs one water less than the free amino acid, and a peptide's mass is built by adding residue masses.

A peptide chain has two different ends. One keeps a free amino group: the N-terminus. The other keeps a free acid group: the C-terminus. A sequence is always written from the N-terminus on the left to the C-terminus on the right.

That makes direction part of identity. Gly-His-Lys (GHK) and Lys-His-Gly (KHG) contain the same atoms and have the same mass, yet they are different molecules. GHK is the peptide in copper tripeptide-1, a common cosmetic ingredient.

The number of possible sequences grows fast. Twenty amino acids give 400 dipeptides, 8,000 tripeptides, 160,000 tetrapeptides and 64 million hexapeptides.

Regulators draw their own lines. The US Food and Drug Administration defines a protein as an alpha amino acid polymer with a specific, defined sequence of more than 40 amino acids, so anything of 40 or fewer counts as a peptide in its rules. Insulin shows how loose the words are: it has 51 amino acids in two chains, held together by disulfide bridges, and it is called both a peptide and a protein.

In living cells. Ribosomes build peptides and proteins by reading a gene, and cells also cut larger proteins into peptides. Digestion does the same to the protein in food, breaking it into peptides and then into free amino acids.

By chemical synthesis. Most synthetic peptides are made by solid-phase peptide synthesis, which Bruce Merrifield published in 1963 and for which he received the Nobel Prize in Chemistry in 1984. The chain is anchored by its C-terminal end to small resin beads and built one amino acid at a time, each arriving with its reactive groups protected. At the end the peptide is cut from the resin, the protecting groups are removed, and the product is purified by HPLC and freeze-dried. Purification leaves counter-ions attached to the peptide, so a peptide powder is never 100% peptide by weight. Peptide purity explained shows what that means on a certificate.

By recombinant DNA technology. Engineered cells are given a gene and produce the peptide or protein for it.

Peptides are grouped in several ways, and one peptide can belong to several groups at once.

• By length: dipeptides, tripeptides, oligopeptides, polypeptides.
• By origin: natural, made by living things; synthetic, made by chemistry; recombinant, made by engineered cells.
• By shape: linear chains, and cyclic peptides closed into a ring, end to end or through side chains. Two cysteines in a chain can also be linked by a disulfide bridge.
• By modification: an acetyl group on the N-terminus, an amide at the C-terminus, a fatty acid chain such as palmitoyl, or a metal held by the peptide, as copper is in copper tripeptide-1.
• By what they are sold as: a registered medicine, a cosmetic ingredient, a food ingredient such as collagen peptides, or a research material for laboratories.

The last grouping is the one that decides the rules. In Iraq each of these is regulated differently, and the same molecule can be lawful in one category and not in another. Are peptides legal in Iraq? sets out the categories.