Engineering the Structure of an N-Terminal β-Turn To Maximize Screw-Sense Preference in Achiral Helical Peptide Chains

Abstract

Oligomers of α-aminoisobutyric acid (Aib) are achiral peptides that typically adopt 3 10 helical conformations in which enantiomeric left-and right-handed conformers are, necessarily, equally populated. Incorporating a single protected chiral residue at the N-terminus of the peptide leads to induction of a screw-sense preference in the helical chain, which may be quantified (in the form of "helical excess") by NMR spectroscopy. Variation of this residue and its N-terminal protecting group leads to the conclusion that maximal levels of screw-sense preference are induced by bulky chiral tertiary amino acids carrying amide protecting groups or by chiral quaternary amino acids carrying carbamate protecting groups. Tertiary L-amino acids at the N-terminus of the oligomer induce a left-handed screw sense, while quaternary L-amino acids induce a righthanded screw sense. A screw-sense preference may also be induced from the second position of the chain, weakly by tertiary amino acids, and much more powerfully by quaternary amino acids. In this position, the L enantiomers of both families induce a right-handed screw sense. Maximal, and essentially quantitative, control is induced by an L-α-methylvaline residue at both positions 1 and 2 of the chain, carrying an N-terminal carbamate protecting group.

Ligand-modulated conformational switching in a fully synthetic membrane-bound receptor

“…19 In solution, these "foldamers" 20 populate almost exclusively 21 two rapidly exchanging conformational states of left or right handed helical screw sense, with the relative population of these two states being remarkably sensitive to chiral influences. [22][23][24][25] A chiral ligand covalently 15 or non-covalently 16 bound to one terminus of an Aib foldamer will propagate its conformational influence through the entire foldamer length. 26 In this way endto-end transmission of binding information over multi-nanometre distances has been accomplished through Aib foldamers dissolved in organic solvents.…”

Signal transduction in oligoamide foldamers by selective non-covalent binding of chiral phosphates at a urea binding site

“…48b Changing the solvent from THF-d8 to CD3CN decreased the value of Δδ at all ratios of proton sponge:1a. Comparison with known values for Δδ in these solvents 51 suggested that while 2a induced a screw sense preference in 1a of 28% helical excess (h.e.) in solution in THF-d8, the induction of screw sense preference in CD3CN reaches only 16% h.e.…”

“…48, 49 We now report the intramolecular, non-covalent induction of a conformational preference in an amide foldamer purely through hydrogen-bonded interactions between a chiral anion and a suitable geometrically matched binding site incorporating a urea function. Four foldamers, 1a-d (Fig 1) were synthesised, in each of which an achiral but helical Aib pentamer 50,51 is capped, at its N-terminus, by a urea function. At the C-terminus, the terminal Aib carries a pair of 13 C-labelled methyl groups to act as a marker of conformational induction.…”

Refoldable Foldamers: Global Conformational Switching by Deletion or Insertion of a Single Hydrogen Bond

“…The two screw‐sense conformers of an Aib oligomer may be desymmetrised by ligation to a chiral terminus,23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33 which leads to an imbalance in the population of the two interconverting screw‐sense conformers 34,35. This imbalance may be quantified by NMR,27 and a C terminal AlaNHR residue, for example, may induce a 99:1 preference for right‐handed screw sense in an attached Aib oligomer chain 25.…”