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 peptide	Subclasses	General features	Example

Cyclic peptides Peptides with the N- and C-termini connected via a bond (N-to-C amide bond, disulfide bond, thioether bond, …)	Unicyclic	Can be chemically synthesized, can include ncAAs, often <20 AA, often lack clear secondary structure elements, often protease resistant	Cyclosporin (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 peptide		G7-B1 (bicyclic 11mer) binds to Grb7-SH2 domain (PDB 5EEL [2])

Lariat peptides Cyclic peptides with linear segments flanking from one or both termini	Lariats	Can be chemically synthesized, can include ncAAs	Oxytocin 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 ring	A member of ribosomally assembled posttranslationally modified peptides (RiPPs), often hard to synthesize, heat resistant	RP 71955 (PDB 1RPC [5] shows structure in solution)
	Class II: no disulfide bond		Caulosegnin I (PDB 2LX6 [6] shows structure in solution)
	Class III: one disulfide bond between the tail and the ring		BI-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 conotoxins	Very stable, can be chemically synthesized or expressed, often resistant to loop swapping	A-conotoxin binds to nicotinic acetylcholine receptor (PDB 2C9T [8] in complex with AChBP homolog)
	Peptides with multiple noncanonical crosslinkers such as lantibiotics	Often naturally synthesized and posttranslationally modified, often include a large variety of	Nisin (PDB 1WCO [9] shows Nisin in complex with lipid-II)

Linear fragments	Helical fragments	Can be expressed or synthesized, originally no ncAAs, often require additional crosslinkers or scaffolds to stabilize the given conformation	Helical fragment of p53 bound to MDM2 (PDB 1YCR [10])
	-Strand fragments		C-terminal of p53 bound to SIRT1 (PDB 4ZZJ [11])
	Loop fragments		Proline rich peptides (PDB 1GBR [12])

Miniproteins	Can be classified based on the order of secondary structure elements, or presence or absence of disulfide bonds	Larger 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 synthesized	Miniprotein anti-ACE binder (PDB 7JZM [13])