Sequence Engineering to Control the Helix Handedness of Peptide Foldamers

Abstract

Peptide foldamers have been studied for over two decades and numerous sequence patterns have been shown to form well-defined three-dimensional arrangements in solution. In particular, helices of various geometries have been described. In this article, different concepts concerning the construction of helical foldameric peptides, for which the possibility of governing the sense of the formed helix was evidenced, are presented and discussed.

The Diverse World of Foldamers: Endless Possibilities of Self-Assembly

“…The secondary structures of foldamers based on higher homologues of α-amino acids (e.g., γ- and δ-amino acids), and the rationale at the basis of their formation and stability, have not been studied at the same level of detail than those of β-peptides [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 ] and aromatic foldamers [ 2 , 6 , 10 , 11 , 12 , 18 , 19 ]. The same usually applies to the knowledge and comprehension of the folding propensities of foldamers based on peptide analogs [ 15 ] and oligomers with heterogeneous backbones, either in the sense of peptidic skeletons featuring different types of aliphatic amino acids [ 16 ] or mixed aliphatic–aromatic structures [ 17 ].…”

“…The nomenclature for β-sheets is the same used for α-peptides and it is not reported here (for reviews dealing with the secondary structures of these foldamers, see Refs. [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 ]).…”

“…The fundamental studies in the first two decades led to the discovery of the several secondary structures typical of homo-oligomers made of β, γ and even higher homologues of α-amino acids, as well as α-peptoids [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 ], as shown in Figure 1 , and various aromatic monomers [ 2 , 6 , 10 , 11 , 12 ], as shown in Figure 2 . Within these structural determinations, single-crystal X-ray data obviously played a starring role, but the entire arsenal of mono- and bidimensional nuclear magnetic resonance (NMR) spectroscopies was determined in order to deduce the correct folding in solution and the conformational stability in different solvents, especially when coupled with molecular dynamics simulations.…”

“…As far as helices formed by β-peptide foldamers and their analogues are concerned, it has been shown that an accurate use of the suitable monomers can lead to several different foldings, characterized by their peculiar hydrogen bonding patterns, as shown in Figure 1 g. This, in turn, generates helical arrangements that differ by their handedness, diameter, pitch, number of residues per turn, macrodipole (the overall dipole generated by the sum of individual dipoles from the amide groups along the helix axis) and exact placement/directionality of side chains [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 ]. As an illustrative example of this ease of control over the secondary structure, when α and β carbons of β-peptide foldamers are tethered in 4, 5 and 6-membered aliphatic cycles with trans stereochemistry, the favored secondary structures are the 12- (4 and 5-membered cycles) and 14-helices (6-membered cycles).…”

“…This nomenclature is also used for higher peptidic homologues. The nomenclature for β-sheets is the same used for α-peptides and it is not reported here (for reviews dealing with the secondary structures of these foldamers, see Refs [1][2][3][4][5][6][7][8][9]…”