BioDesign Research / 2022 / Article / Tab 1

Review Article

Design of Protein Segments and Peptides for Binding to Protein Targets

Table 1

Description of different classes of peptides, their descriptions, and some of their general features, and examples of them with structure.

Type of peptideSubclassesGeneral featuresExample

Cyclic peptides
Peptides with the N- and C-termini connected via a bond (N-to-C amide bond, disulfide bond, thioether bond, …)
UnicyclicCan be chemically synthesized, can include ncAAs, often <20 AA, often lack clear secondary structure elements, often protease resistantCyclosporin (11mer N-to-C cyclized peptide) binds to cyclophilin (PDB 1CWA [1])
Multicyclic: where there are additional internal bridges such as disulfide bonds in a cyclic peptideG7-B1 (bicyclic 11mer) binds to Grb7-SH2 domain (PDB 5EEL [2])

Lariat peptides
Cyclic peptides with linear segments flanking from one or both termini
LariatsCan be chemically synthesized, can include ncAAsOxytocin binds to oxytocin receptor (NMR structure of unbound oxytocin: 2MGO [3])

Lasso peptides
A ring with a C-terminal tail that goes through the ring [4]
Class I: 2 disulfide bonds between the tail and the ringA member of ribosomally assembled posttranslationally modified peptides (RiPPs), often hard to synthesize, heat resistantRP 71955 (PDB 1RPC [5] shows structure in solution)
Class II: no disulfide bondCaulosegnin I (PDB 2LX6 [6] shows structure in solution)
Class III: one disulfide bond between the tail and the ringBI-32169 (PDB 3NJW [7] shows structure in solution)

Constrained peptides
Peptides that are stabilized by multiple internal cross-linking bridges
Disulfide constrained peptides such as conotoxinsVery stable, can be chemically synthesized or expressed, often resistant to loop swappingA-conotoxin binds to nicotinic acetylcholine receptor (PDB 2C9T [8] in complex with AChBP homolog)
Peptides with multiple noncanonical crosslinkers such as lantibioticsOften naturally synthesized and posttranslationally modified, often include a large variety ofNisin (PDB 1WCO [9] shows Nisin in complex with lipid-II)

Linear fragmentsHelical fragmentsCan be expressed or synthesized, originally no ncAAs, often require additional crosslinkers or scaffolds to stabilize the given conformationHelical fragment of p53 bound to MDM2 (PDB 1YCR [10])
-Strand fragmentsC-terminal of p53 bound to SIRT1 (PDB 4ZZJ [11])
Loop fragmentsProline rich peptides (PDB 1GBR [12])

MiniproteinsCan be classified based on the order of secondary structure elements, or presence or absence of disulfide bondsLarger peptides often around 20-50 amino acids, stabilized by a packed core, can have disulfide bonds as well, often expressed but in the case of shorter ones can be synthesizedMiniprotein anti-ACE binder (PDB 7JZM [13])