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Conformational Switching of a Foldamer in a Multicomponent System by pH-Filtered Selection between Competing Noncovalent Interactions.

Brioche J, Pike SJ, Tshepelevitsh S, Leito I, Morris GA, Webb SJ, Clayden J - J. Am. Chem. Soc. (2015)

Bottom Line: As a consequence of this noncovalent interaction, a global absolute screw sense preference, detectable by (13)C NMR, is induced in the foldamer.Addition of base, or acid, to the mixture of ligands competitively modulates their interaction with the binding site, and reversibly switches the foldamer chain between its left and right-handed conformations.As a result, the foldamer-ligand mixture behaves as a biomimetic chemical system with emergent properties, functioning as a "proton-counting" molecular device capable of providing a tunable, pH-dependent conformational response to its environment.

View Article: PubMed Central - PubMed

Affiliation: †School of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, United Kingdom.

ABSTRACT
Biomolecular systems are able to respond to their chemical environment through reversible, selective, noncovalent intermolecular interactions. Typically, these interactions induce conformational changes that initiate a signaling cascade, allowing the regulation of biochemical pathways. In this work, we describe an artificial molecular system that mimics this ability to translate selective noncovalent interactions into reversible conformational changes. An achiral but helical foldamer carrying a basic binding site interacts selectively with the most acidic member of a suite of chiral ligands. As a consequence of this noncovalent interaction, a global absolute screw sense preference, detectable by (13)C NMR, is induced in the foldamer. Addition of base, or acid, to the mixture of ligands competitively modulates their interaction with the binding site, and reversibly switches the foldamer chain between its left and right-handed conformations. As a result, the foldamer-ligand mixture behaves as a biomimetic chemical system with emergent properties, functioning as a "proton-counting" molecular device capable of providing a tunable, pH-dependent conformational response to its environment.

No MeSH data available.


(a)Achiral foldamers; (b) binding sites; and (c) chiral acidsand anions.
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fig1: (a)Achiral foldamers; (b) binding sites; and (c) chiral acidsand anions.

Mentions: A small library of potentialbinding sites B0–7 were ligated tothe N-terminus of 4–9 Aib residueoligomers to form achiral helical foldamers (F0–7) (for synthetic details, see the SupportingInformation, SI). Several chiral acids (HA1–6)62 or anions (A7–, A8–)63,64 with a range of gross structural featuresand pKa values were chosen as potentialchiral ligands (Figure 1).65,66 To allow us to quantify the global conformational change in anyof F0–F7 induced by interaction withany of HA1–6, a 13C NMRreporter of helical screw-sense preference was incorporated into thefoldamers F0–7 at a position remotefrom the binding site. The C-terminal Aib residue was labeled with 13C at both enantiotopic methyl groups.67 At ambient temperature under normal conditions of rapidscrew sense inversion, the anisochronicity (Δδ) of thetwo diastereotopic 13CH3 signals of the NMRprobe is proportional to the imbalance between the population of M and P conformers of the foldamer F (the helical excess, h.e.).58 The anisochronicity Δδ was typically measured by recording 13C NMR spectra at 296 K in CDCl3 of mixtures of HA and F at concentration of [F]= 10 mM (sufficiently low to avoid foldamer aggregation68) and in a ratio HA:F = 1.2:1. The values of Δδ are reported in Table 1 as anisochronicity (in ppb) and as a screw-sensepreference (helical excess, h.e.) calculated from Δδ asdescribed in the SI.59


Conformational Switching of a Foldamer in a Multicomponent System by pH-Filtered Selection between Competing Noncovalent Interactions.

Brioche J, Pike SJ, Tshepelevitsh S, Leito I, Morris GA, Webb SJ, Clayden J - J. Am. Chem. Soc. (2015)

(a)Achiral foldamers; (b) binding sites; and (c) chiral acidsand anions.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4520694&req=5

fig1: (a)Achiral foldamers; (b) binding sites; and (c) chiral acidsand anions.
Mentions: A small library of potentialbinding sites B0–7 were ligated tothe N-terminus of 4–9 Aib residueoligomers to form achiral helical foldamers (F0–7) (for synthetic details, see the SupportingInformation, SI). Several chiral acids (HA1–6)62 or anions (A7–, A8–)63,64 with a range of gross structural featuresand pKa values were chosen as potentialchiral ligands (Figure 1).65,66 To allow us to quantify the global conformational change in anyof F0–F7 induced by interaction withany of HA1–6, a 13C NMRreporter of helical screw-sense preference was incorporated into thefoldamers F0–7 at a position remotefrom the binding site. The C-terminal Aib residue was labeled with 13C at both enantiotopic methyl groups.67 At ambient temperature under normal conditions of rapidscrew sense inversion, the anisochronicity (Δδ) of thetwo diastereotopic 13CH3 signals of the NMRprobe is proportional to the imbalance between the population of M and P conformers of the foldamer F (the helical excess, h.e.).58 The anisochronicity Δδ was typically measured by recording 13C NMR spectra at 296 K in CDCl3 of mixtures of HA and F at concentration of [F]= 10 mM (sufficiently low to avoid foldamer aggregation68) and in a ratio HA:F = 1.2:1. The values of Δδ are reported in Table 1 as anisochronicity (in ppb) and as a screw-sensepreference (helical excess, h.e.) calculated from Δδ asdescribed in the SI.59

Bottom Line: As a consequence of this noncovalent interaction, a global absolute screw sense preference, detectable by (13)C NMR, is induced in the foldamer.Addition of base, or acid, to the mixture of ligands competitively modulates their interaction with the binding site, and reversibly switches the foldamer chain between its left and right-handed conformations.As a result, the foldamer-ligand mixture behaves as a biomimetic chemical system with emergent properties, functioning as a "proton-counting" molecular device capable of providing a tunable, pH-dependent conformational response to its environment.

View Article: PubMed Central - PubMed

Affiliation: †School of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, United Kingdom.

ABSTRACT
Biomolecular systems are able to respond to their chemical environment through reversible, selective, noncovalent intermolecular interactions. Typically, these interactions induce conformational changes that initiate a signaling cascade, allowing the regulation of biochemical pathways. In this work, we describe an artificial molecular system that mimics this ability to translate selective noncovalent interactions into reversible conformational changes. An achiral but helical foldamer carrying a basic binding site interacts selectively with the most acidic member of a suite of chiral ligands. As a consequence of this noncovalent interaction, a global absolute screw sense preference, detectable by (13)C NMR, is induced in the foldamer. Addition of base, or acid, to the mixture of ligands competitively modulates their interaction with the binding site, and reversibly switches the foldamer chain between its left and right-handed conformations. As a result, the foldamer-ligand mixture behaves as a biomimetic chemical system with emergent properties, functioning as a "proton-counting" molecular device capable of providing a tunable, pH-dependent conformational response to its environment.

No MeSH data available.