How to read a peptide sequence and the modifications written into it

Symbols at a glance

The sections below give the source for each row.

Two alphabets

The conventions come from the 1983 recommendations of the IUPAC-IUB Joint Commission on Biochemical Nomenclature.²³ Each amino acid has a three-letter symbol, and a hyphen between two symbols stands for the peptide bond.² A one-letter code was approved in 1968 for long sequences in tables and lists, and the commission advised against using it in simple text because it is less easily understood.²

PubChem’s record for BPC-157 lists the sequence both ways among its names: Gly-Glu-Pro-Pro-Pro-Gly-Lys-Pro-Ala-Asp-Asp-Ala-Gly-Leu-Val and H-GEPPPGKPADDAGLV-OH.⁴ Fifteen symbols stand for fifteen residues. The H- and the -OH in the second form stress that the ends are unsubstituted: a free amino group and a free carboxylic acid.²

Direction and numbering

The symbol on the left is the residue with the free amino group, the N-terminus; the one on the right has the free carboxyl group, the C-terminus.² Residues are numbered from the N-terminal end.² A synthesizer builds the chain in the opposite direction, as the guide to solid-phase peptide synthesis explains.

An analogue keeps the numbers of its parent. IUPAC writes a replacement as the new residue and its position in square brackets before the parent’s name, and a fragment as the parent’s name followed by its first and last positions.² PubChem lists sermorelin under a name of the second kind, GHRH(1-29)NH2.⁵

Cell study Sawyer and colleagues named their 1980 analogue of alpha-melanocyte-stimulating hormone [Nle4, D-Phe7]-alpha-MSH: norleucine at position 4 and D-phenylalanine at position 7.⁶ They reported that it resisted degradation by serum enzymes.⁶

The FDA label for afamelanotide writes a peptide with that pattern in full, Ac-Ser-Tyr-Ser-Nle-Glu-His-(D)Phe-Arg-Trp-Gly-Lys-Pro-Val-NH2, and PubChem lists Melanotan I among that compound’s names.⁷⁸

Inherited numbers need not start at 1. Semaglutide’s label places its changes at positions 8, 26 and 34.⁹ Those read as GLP-1 numbers: the label for the related analogue liraglutide, changed at positions 26 and 34, writes the parent hormone as GLP-1(7-37), a fragment name in which the chain begins at residue 7.²¹⁰ Read that way, position 8 is the second residue of the chain. Tirzepatide’s label puts Aib at positions 2 and 13 of a chain based on the GIP sequence.¹¹

End caps: acetyl and amide

“Ac-” is an acetyl group on the N-terminal amino group. “-NH2” at the right-hand end means the C-terminal carboxyl group has been converted to an amide.²

Cell study Heavner and colleagues used both caps on analogues of the pentapeptide thymopentin to raise resistance to exopeptidases, and reported that two amidated analogues, one of them also acetylated, were highly stable when incubated in human serum.¹² A 2011 study describes thymosin alpha-1 as a 28-residue peptide acetylated at its N-terminus, and confirmed by tandem mass spectrometry the acetyl group on the first serine of a recombinant version.¹³

One cap can be the whole difference between two compounds. The paper reporting a pilot phase I study of Melanotan II gives its structure ending in -NH2.¹⁴ The FDA label for bremelanotide, which PubChem also lists as PT-141, shows the same residues ending in -OH and describes a free acid at the carboxyl terminus.¹¹⁵ PubChem gives the two compounds weights of 1024.2 and 1025.2 g/mol.¹⁵¹⁶ Put through IUPAC’s one-letter table, which has X for an atypical residue and nothing for end groups, D forms or rings, both reduce to XDHFRWK.²

D-residues, Aib and other non-coded building blocks

Ipamorelin was published as Aib-His-D-2-Nal-D-Phe-Lys-NH2.¹⁷ Aib is aminoisobutyric acid, which PubChem’s systematic name for ipamorelin writes as 2-methylalanine, and D-2-Nal is the D form of 3-(2-naphthyl)alanine.¹¹¹⁸ GHRP-6 is the hexapeptide published in 1984 as His-D-Trp-Ala-Trp-D-Phe-Lys-NH2.¹⁹²⁰

Cell study One reason for such substitutions is resistance to enzymes: in plasma, a D-amino acid at position 1 or 2 of growth hormone-releasing hormone prevented cleavage by dipeptidyl peptidase IV.²¹

Review Another is shape: a structural review found that peptides rich in amino acids methylated at the alpha carbon, the family to which Aib belongs, preferentially adopt helical structures.²²

Other symbols need the same care. Nle is norleucine; IUPAC’s 1983 text proposed retiring that symbol in favour of Ahx, yet current labels still print Nle.¹² PubChem lists SS-31 (elamipretide) as D-Arg-Dmt-Lys-Phe-NH2, and the record’s systematic name shows what Dmt stands for: 2,6-dimethyl-L-tyrosine.²³ Both IUPAC and the European Medicines Agency’s guideline on synthetic peptides ask that non-standard symbols be defined where they are used.²²⁴

Rings: lactam and disulfide bridges

IUPAC writes a ring made only of ordinary peptide bonds as cyclo(…). It calls a ring heterodetic when another kind of bond closes it, such as a disulfide or an amide formed through a side chain.²

Melanotan II is of the second kind: its paper calls it lactam-bridged, and a systematic name in PubChem describes a cyclic (2-7) peptide, closed between the second and seventh residues.¹⁴¹⁶ Oxytocin is closed by a disulfide between its two cysteines: PubChem lists it as Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu-Gly-NH2, cyclic 1-6 disulfide.²⁵ In one-letter code the same residues read CYIQNCPLG, with neither the bridge nor the amide.²

Attached chains: acyl groups, lipids, linkers and PEG

IUPAC shows a group on a side chain in parentheses after its residue, as in Pro(4-OH) for 4-hydroxyproline.² Labels describe larger groups in words.

“C18” and “C20” count carbon atoms, and a diacid has an acid group at each end. In the CJC-1295 paper the parent is written hGRF(1-29), the first 29 residues of human growth hormone-releasing factor, and the lysine’s side-chain nitrogen is written N-epsilon.²⁷ What that reactive group is for is covered in half-life extension strategies.

Tesamorelin shows why the full name matters. PubChem lists the bare GHRH(1-44) among its synonyms, beside names such as (3E)-hex-3-enoylsomatoliberin that spell out the added group.²⁸

Review PEG is polyethylene glycol, and pegylation is the attachment of PEG chains to a peptide or protein.²⁹ The EMA guideline expects the full chemical structure of non-peptidic side chains and linkers, and names PEG chains among the non-peptide parts joined to peptides.²⁴

What a name leaves out

A name does not give the salt form. The labels for bremelanotide and tesamorelin describe acetate salts and quote the weight of the free base.¹²⁶ Nor is a name proof of identity: that takes measurement, described in the guide to analytical methods for peptides.

Human evidence

A name describes a structure, not an effect, and this page cites no study for what a compound does in people. One source, the Melanotan II pilot study, was run in volunteers, and it is used here only for the structure it prints.¹⁴ What has been studied in people is set out on each compound’s own page.