Polypeptide chains in cyclic peptides form cyclic ring structures. Cyclic peptides are found in nature and can be created synthetically. Cyclizing a linear peptide often creates a compound that is more rigid and more resistant to hydrolysis.
Disulfide bridge (also called disulfide bond or S-S bond) is a covalent linkage between two mercapto (also known as thiol) groups, that forms most commonly when the groups lose one hydrogen each due to oxidation. Amino acids containing the mercapto group on their sidechain, most notably Cysteine, may and often will react with other such amino acids within the same peptide sequence (reactions across different peptide chains are also possible) thus forming cyclic structures.
Large numbers of peptide and protein molecules in nature contain disulfide bridges. Forming disulfide bridges is also a popular way of creating cyclic peptides in a lab, due to the established procedures that match very well the contemporary methods of solid phase peptide synthesis.
To review the structure of a disulfide bridge containing peptide, take a look at how the sequence of Human Calcitonin Gene Related Peptide (α-CGRP) is written:
This is a thirty-seven amino acid sequence. Amino acid residues in peptide sequences are numbered from left to right; in this peptide the leftmost residue is Alanine (A), with N-terminal free amine, has the index of one; and the last residue Phenylalanine (F), in this case with capped C-terminal amide, is the thirty-seventh amino acid residue.
Note that there are two Cysteine (C) residues in the α-CGRP peptide sequence, in the positions two and seven respectfully. To indicate the disulfide bridge between these two cysteines, a peptide modification “Cys2-Cys7” is specified in the square braces in the beginning of the string. To distinguish modifications that relate to the whole peptide (such as the disulfide bridge we see in this peptide) from modifications of the first amino acid residue, there is a space between the closing square brace and the first amino acid residue.
As an aside; if the first Alanine residue in the peptide was labeled with 13C, 15N stable isotopes, we could write the sequence as follows:
The modification adjacent to the first amino acid is for that amino acid specifically, while the modification separated with a space is for the whole peptide.
Peptides and proteins often contain multiple disulfide bridges. Such is the following Sarafotoxin S6b peptide:
[Cys1-Cys15, Cys3-Cys11] CSCKDMTDKECLYFCHQDVIW
Comas separate different modifications inside the square braces. We see that in Sarafotoxin S6b peptide there are bridges between the first and fifteenth as well as between the third and eleventh Cysteine residues.
Though weaker than peptide bonds, disulfide bridges are considerably stable with typical dissociation energy of 60 kcal/mole (251 kJ mol−1). Introduction of disulfide bridges produces heterodetic cyclic peptides, as opposed to homodetic cyclic peptides where only peptide bonds participate in ring formation.
Head-to-tail cyclic peptides
The prime examples of homodetic cyclic peptides are head-to-tail monocyclic peptides, which contain no main chain termini. All amino acid residues in such chain are connected by peptide bonds to their neighbors, forming a fully enclosed structure.
In written form, head-to-tail cyclization is conveyed by surrounding the whole peptide sequence in round braces and adding the word “cyclo” before them; like in the following Сycloleonuripeptide A molecule:
Both peptide bonds and disulfide bridges can form cyclic structures within a given peptide molecule simultaneously. Bicyclic Malformin A (from metabolic product family of Aspergillus niger fungus) microbial pentapeptide is one such example:
Here we see the sidechains of two D-Cysteinyls forming a bridge, while simultaneously the whole peptide is cyclized head-to-tail.
Peptide bonds may occur not only between alpha carboxyl of one residue and the alpha amine of another. Another notable example is peptide bonds that may occur between positively charged sidechain amine functional group containing amino acids (Lysine, Ornithine), and sidechain carboxyls of acidic amino acids (Aspartic Acid, Glutamic Acid).
The D-Phenylalanine containing seven-amino-acid MC-R agonist capped peptide above demonstrates a sidechain-to-sidechain lactam bridge.
If the first (head) amino acid residue primary amine is not occupied with anything else, an acidic residue within the peptide sequence and the peptide N-terminal may form the so-called head-to-sidechain bridge.
Inverse to head-to-sidechain bridges, sidechain-to-tail bridges may occur, including lactam bridges between a residue with a strongly charged basic side-chain and the C-terminal carboxyl group.
Another interesting case of sidechain-to-tail cyclic peptide is demonstrated by the E. faecalis gelatinase biosynthesis-activating pheromone (GBAP):
It is an 11-residue cyclic peptide containing a lactone structure, in which the sidechain hydroxyl group of the third residue Serine is linked to the the alpha-carboxyl group of the C-terminal Methionine amino acid.
Cyclic peptide calculation
The peptide and protein fragment analytical tool on this website understands cyclic peptides. You can use the example peptide sequences from this and other articles on the peptidenexus.com as templates or guides on how to enter your own sequences. In most cases you can copy and paste sequences straight from various catalogs and articles and the peptide calculator will understand the standard notation.