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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.


Conformational switching of foldamer F4* with threecompeting chiral ligands in a single phase. PS = proton sponge. [F4*] = 10 mM, CDCl3, 296 K; all subsequent additionsare of 1.5 equiv relative to F4*. Portions of the 13C NMR spectra of the mixtures containing the labeled signalsof F4* are shown, with anisochronicity Δδreported as the difference in chemical shift between the major andminor labeled signals of F4*, δmaj –δmin, measured in ppb. Protonated species availablefor interaction with the F4* binding site (representedby the pyridine in the colored rectangle) are indicated by blue/green(for chiral species) or gray (for achiral species) disks, and acids HA are stacked in order of pKa. The number of protons available is represented by the number ofdiscs, building up from the bottom of the stack. Proposed conformation-inducinginteractions with F4* (whether these are hydrogen-bondedor ion-paired is left undefined) are coded by matched colors: blueindicates induction of a P screw-sense; green indicatesinduction of an M screw-sense; and red indicatesno screw-sense induction. The most significant interaction is assumedto be between F4* and the top (typically the most acidic)protonated species in each multiply protonated stack.
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fig8: Conformational switching of foldamer F4* with threecompeting chiral ligands in a single phase. PS = proton sponge. [F4*] = 10 mM, CDCl3, 296 K; all subsequent additionsare of 1.5 equiv relative to F4*. Portions of the 13C NMR spectra of the mixtures containing the labeled signalsof F4* are shown, with anisochronicity Δδreported as the difference in chemical shift between the major andminor labeled signals of F4*, δmaj –δmin, measured in ppb. Protonated species availablefor interaction with the F4* binding site (representedby the pyridine in the colored rectangle) are indicated by blue/green(for chiral species) or gray (for achiral species) disks, and acids HA are stacked in order of pKa. The number of protons available is represented by the number ofdiscs, building up from the bottom of the stack. Proposed conformation-inducinginteractions with F4* (whether these are hydrogen-bondedor ion-paired is left undefined) are coded by matched colors: blueindicates induction of a P screw-sense; green indicatesinduction of an M screw-sense; and red indicatesno screw-sense induction. The most significant interaction is assumedto be between F4* and the top (typically the most acidic)protonated species in each multiply protonated stack.

Mentions: Aiming to avoid the deterioratingconformational control that appearsto result from the accumulation of hydrogen-bond donating ammoniumions, we repeated the acid–base switching experiment with protonsponge86 (PS, 1,8-bis(dimethylamino)naphthalene),selected as an alternative base to NH3 that will sequesterthe accepted proton with an internal hydrogen bond. The results areshown in Figure 8, where stages a–dmatch the switching process of Figure 7a–d.Addition of PS (1.5 equiv) to the four component system F4*+HA1+HA4+HA6 of Figure 8d induced a conformational switch from M to P (Figure 8e) as observedwith ammonia (Figure 7e), but with much greaterretention of conformational control [Δδ = +667 ppb inthe presence of PSH+ (Figure 8e),compared with +890 ppb in the absence of cations (Figure 8c) and only +190 ppb in the presence of NH4+ (Figure 7e)]. The second additionof PS (1.5 equiv) switched screw-sense from P to M (Figure 8f) but this time withonly marginally greater conformational control than with NH3 (Figure 7f). Unlike with NH3,the third addition of PS (1.5 equiv) did not result in the systemswitching to the resting ± state: an induced M screw sense was still observed (Figure 8g).Working back up the acidity scale, a first addition of HCl (1.5 equiv)had no influence on the system, which remained M (Figure 8h), and a second addition of HCl (1.5 equiv) induceda switch from M to P with good recoveryof the conformational control typical of HA4↔F4*. However, a third addition of HCl (1.5 equiv) did notresult in the switch from P to M as seen with ammonia as base (Figure 7h)—instead F4* remained in the P screw-sense, but witha reduced magnitude of conformational control extent (Figure 8i).


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)

Conformational switching of foldamer F4* with threecompeting chiral ligands in a single phase. PS = proton sponge. [F4*] = 10 mM, CDCl3, 296 K; all subsequent additionsare of 1.5 equiv relative to F4*. Portions of the 13C NMR spectra of the mixtures containing the labeled signalsof F4* are shown, with anisochronicity Δδreported as the difference in chemical shift between the major andminor labeled signals of F4*, δmaj –δmin, measured in ppb. Protonated species availablefor interaction with the F4* binding site (representedby the pyridine in the colored rectangle) are indicated by blue/green(for chiral species) or gray (for achiral species) disks, and acids HA are stacked in order of pKa. The number of protons available is represented by the number ofdiscs, building up from the bottom of the stack. Proposed conformation-inducinginteractions with F4* (whether these are hydrogen-bondedor ion-paired is left undefined) are coded by matched colors: blueindicates induction of a P screw-sense; green indicatesinduction of an M screw-sense; and red indicatesno screw-sense induction. The most significant interaction is assumedto be between F4* and the top (typically the most acidic)protonated species in each multiply protonated stack.
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fig8: Conformational switching of foldamer F4* with threecompeting chiral ligands in a single phase. PS = proton sponge. [F4*] = 10 mM, CDCl3, 296 K; all subsequent additionsare of 1.5 equiv relative to F4*. Portions of the 13C NMR spectra of the mixtures containing the labeled signalsof F4* are shown, with anisochronicity Δδreported as the difference in chemical shift between the major andminor labeled signals of F4*, δmaj –δmin, measured in ppb. Protonated species availablefor interaction with the F4* binding site (representedby the pyridine in the colored rectangle) are indicated by blue/green(for chiral species) or gray (for achiral species) disks, and acids HA are stacked in order of pKa. The number of protons available is represented by the number ofdiscs, building up from the bottom of the stack. Proposed conformation-inducinginteractions with F4* (whether these are hydrogen-bondedor ion-paired is left undefined) are coded by matched colors: blueindicates induction of a P screw-sense; green indicatesinduction of an M screw-sense; and red indicatesno screw-sense induction. The most significant interaction is assumedto be between F4* and the top (typically the most acidic)protonated species in each multiply protonated stack.
Mentions: Aiming to avoid the deterioratingconformational control that appearsto result from the accumulation of hydrogen-bond donating ammoniumions, we repeated the acid–base switching experiment with protonsponge86 (PS, 1,8-bis(dimethylamino)naphthalene),selected as an alternative base to NH3 that will sequesterthe accepted proton with an internal hydrogen bond. The results areshown in Figure 8, where stages a–dmatch the switching process of Figure 7a–d.Addition of PS (1.5 equiv) to the four component system F4*+HA1+HA4+HA6 of Figure 8d induced a conformational switch from M to P (Figure 8e) as observedwith ammonia (Figure 7e), but with much greaterretention of conformational control [Δδ = +667 ppb inthe presence of PSH+ (Figure 8e),compared with +890 ppb in the absence of cations (Figure 8c) and only +190 ppb in the presence of NH4+ (Figure 7e)]. The second additionof PS (1.5 equiv) switched screw-sense from P to M (Figure 8f) but this time withonly marginally greater conformational control than with NH3 (Figure 7f). Unlike with NH3,the third addition of PS (1.5 equiv) did not result in the systemswitching to the resting ± state: an induced M screw sense was still observed (Figure 8g).Working back up the acidity scale, a first addition of HCl (1.5 equiv)had no influence on the system, which remained M (Figure 8h), and a second addition of HCl (1.5 equiv) induceda switch from M to P with good recoveryof the conformational control typical of HA4↔F4*. However, a third addition of HCl (1.5 equiv) did notresult in the switch from P to M as seen with ammonia as base (Figure 7h)—instead F4* remained in the P screw-sense, but witha reduced magnitude of conformational control extent (Figure 8i).

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.