Sulfate-induced large amplitude conformational change in a Solomon link

This is a self-archived version of an original article. This version may differ from the original in pagination and typographic details. Author(s): Title: Year: Version: Copyright: Rights: Rights url: Please cite the original version: CC BY 3.0 https://creativecommons.org/licenses/by/3.0/ Sulfate-induced large amplitude conformational change in a Solomon link © 2023 Royal Society of Chemistry Published version Do, Cuong Dat; Pál, Dávid; Belyaev, Andrey; Pupier, Marion; Kiesilä, Anniina; Kalenius, Elina; Galmés, Bartomeu; Frontera, Antonio; Poblador-Bahamonde, Amalia; Cougnon, Fabien B. L. Do, C. D., Pál, D., Belyaev, A., Pupier, M., Kiesilä, A., Kalenius, E., Galmés, B., Frontera, A., Poblador-Bahamonde, A., & Cougnon, F. B. L. (2023). Sulfate-induced large amplitude conformational change in a Solomon link. Chemical Communications, 59(87), 13010-13013. https://doi.org/10.1039/d3cc04555b 2023 This journal is © The Royal Society of Chemistry 2023 Chem. Commun. Cite this: DOI: 10.1039/d3cc04555b Sulfate-induced large amplitude conformational change in a Solomon link† Cuong Dat Do, a Da ´vid Pa ´l, a Andrey Belyaev, b Marion Pupier, a Anniina Kiesila ¨, b Elina Kalenius, b Bartomeu Galme ´s, c Antonio Frontera, c Amalia Poblador-Bahamonde a and Fabien B. L. Cougnon ‡* ab A doubly-interlocked [2]catenane – or Solomon link – undergoes a complex conformational change upon addition of sulfate in methanol. This transformation generates a single pocket where two SO 42 anions bind through multiple hydrogen bonds and electrostatic interactions. Despite the close proximity of the two anions, binding is highly cooperative. Biopolymer conformational changes are essential to many biological processes such as the cooperative binding of four molecules of dioxygen to haemoglobin, 1 and the remote transfer of information mediated by G protein-coupled receptors. 2,3 Taking inspiration from nature, chemists have designed a broad range of synthetic folded molecules, or foldamers, 4–11 able to change conformation. 12–16 However, the propensity of foldamers to unfold in response to external stimuli limits both the diversity and the amplitude of the accessible transformations. 17,18 Nonbiomimetic folded molecules such as multiply entangled macrocycles 19–25 may provide a means to solve this issue. Multiply entangled macrocycles can be considered to be folded because the presence of entanglements reduces their conformational freedom and can block them in specific conformational states. Unlike foldamers, these structures cannot unfold unless a covalent bond is broken but can be deformed in the three dimensions of space by moving the individual threads relative to one another. This process, referred to as ‘‘Reidemeister moves’’ 26,27 in mathematics, should in principle allow transitions between multiple conformational states of different shapes and symmetries. Harnessing such complex conformational behaviour would provide unprecedented opportunities to precisely control the position of functional groups in space and time. Yet, Reidemeister moves have been rarely observed in macromolecules. 28,29 Our group has recently reported the synthesis of a doublyinterlocked [2]catenane, or Solomon link (SL), 30 able to undergo a relatively modest conformational change between two C 4 - symmetric states in acetonitrile/water mixtures. 31 We show now that the addition of sulfate to the same Solomon link in methanol triggers a conformational change of greater amplitude (Fig. 1 and Fig. S1, ESI†), which transforms the C 4 -symmetric Fig. 1 Sulfate-induced conformational change of a Solomon link in methanol (BP86-D3/def2-TZVP optimized geometries). The insert shows a cartoon representation of conformers 1and 2. a Department of Organic Chemistry, University of Geneva, 30 Quai Ernest-Ansermet, 1211 Geneva 4, Switzerland b Department of Chemistry, Nanoscience Center, University of Jyva ¨skyla ¨, P.O. Box 35, FI-40014 JYU, Finland. E-mail: fabien.b.l[email protected] c Department de Quı ´mica, Universitat de les Illes Balears, Carretera de Valldemossa km 7.5, 07122 Palma de Mallorca, Baleares, Spain †Electronic supplementary information (ESI) available. See DOI: https://doi.org/ 10.1039/d3cc04555b ‡Current address: Department of Chemistry, Nanoscience Center, University of Jyva ¨skyla ¨, P.O. Box 35, FI-40014 JYU, Finland. Received 14th September 2023, Accepted 5th October 2023 DOI: 10.1039/d3cc04555b rsc.li/chemcomm ChemComm COMMUNICATION Open Access Article. Published on 06 October 2023. Downloaded on 10/23/2023 1:12:27 PM. This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. View Article Online View Journal Chem. Commun. This journal is © The Royal Society of Chemistry 2023 conformer 1previously observed in pure water 31 into a new D 2 - symmetric conformer (2) different from any of the conformers previously reported. This discovery demonstrates the rich conformational behaviour of multiply entangled macrocycles and establishes their potential as a platform for developing sophisticated multi-responsive systems. The 1 H NMR spectrum of Solomon link SL 8+ 8CF 3 CO 2  in CD 3 OD (Fig. 2A) is consistent with conformer 1. The full NMR characterization is presented in the ESI†(Fig. S2–S5). An optimum packing of the aromatic units results in well-dispersed resonances spreading over ca. 7 ppm, from 3.97 ppm to 10.87 ppm. The isophthalic units, each surrounded by two quinoliniums and a xylyl unit, experience a substantial upfield shift. Isophthalic protons k(3.97 ppm) and l(5.91 ppm) are particularly shielded because they are directly oriented towards the xylyl units in a T-shaped relationship. NOE correlations j2 NH 2a2band k02NH02a02g0recorded in partially non-deuterated CD 3 OH (Fig. S3, ESI†)showthatacylhydrazone protons NH and NH0point in divergent directions. The presence of lower intensity, broad signals (labelled with a star in Fig. 2A) indicates the existence of other minor conformers that may be amplified in response to an external stimulus. We reasoned that the addition of an appropriate anion could trigger the amplification of a conformer with a suitable pocket for anion binding, i.e., with all the NH and NH0hydrogen-bond donors converging towards the centre of the cavity. This hypothesis was tested by carrying out 1 H NMR titrations with a range of common anions (Cl  ,Br  ,I  ,CF 3 SO 3  ,PF 6  ,SCN  ,NO 3  , ReO 4  ,ClO 4  ,andSO 42 as tetra-n-butylammonium salts, Fig. S6, ESI†). None of the anions tested induced any response with the notable exception of SO 42 . The addition of sulfate led to the appearance of a new set of signals corresponding to D 2 -symmetric conformer 2(Fig.2B),whichwasfullycharacterizedinsolutionby NMR (Fig. S9–S12, ESI†) and modeled using dispersion-corrected DFT (BP86-D3/def2-TZVP) methodology. 32,33 Upon binding to sulfate, the Solomon link undergoes a large amplitude conformational change that carries atoms across up to 1.6 nm (Fig. S1, ESI†). In conformation 2, the quinolinium units stack on each side of the Solomon link. The protons of the quinoliniums buried in the stack (b–g) are significantly shielded compared to those of the quinoliniums located on the outer surface (b0–g0). Quinolinium proton bis the most upfield shifted signal (d=3.74ppm) because it is facing the xylyl unit in a T-shape relationship. The isophthalic units are entirely exposed to the solvent and no longer experience the characteristic shielding observed in conformation 1.Finally,NOEcorrelationsg2a2NH 2j2NH02a02 g0(Fig. S10, ESI†) confirm that both acylhydrazone NH and NH0 hydrogen bond donors are oriented towards the centre of the cavity of 2, providing an ideal binding site where sulfate can nest. Electrospray ionization mass spectrometry (ESI-HRMS) corroborates that the Solomon link preferentially binds SO 42 over the other anions tested (Fig. S13–S15, ESI†), as observed by NMR. More importantly, peaks at m/z624.2026 and m/z 831.9337, corresponding to [SL + 2SO 4 ] 4+ and [SL-H + 2SO 4 ] 3+ , respectively, disclose that the Solomon link binds two equivalents of sulfate (Fig. 3). The central cavity of conformer 2 displays two identical sites where SO 42 can bind via the formation of four N–HO–S and ten C–HO–S hydrogen bonds (Fig. S1, ESI†). The tetrahedral disposition of the four acylhydrazone NH hydrogen bond donors of each binding site nicely matches the tetrahedral geometry of the dianion. The preferential binding of SO 42 may thus be explained, at least partially, by the high complementarity between the dianion and the binding sites, in terms of size and geometry. The absence of response with the tetrahedral monoanions ReO 4  and ClO 4  is likely explained by a weaker electrostatic interaction. Conformers 1and 2slowly exchange on the NMR timescale. The fraction yof sulfate-bound conformer 2can therefore be easily measured from the relative integration of the NMR Fig. 2 1 H NMR spectra of the Solomon link (A) before and (B) after addition of 2.6 equiv. of sulfate (CD 3 OD, 500 MHz, 298 K). The signals corresponding to conformers 1and 2are coloured in pink and blue, respectively. The coloured shades on the ChemDraw structure representations highlight key NOE correlations. Communication ChemComm Open Access Article. Published on 06 October 2023. Downloaded on 10/23/2023 1:12:27 PM. This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. View Article Online This journal is © The Royal Society of Chemistry 2023 Chem. Commun. signals as a function of the total concentration of sulfate [SO 42 ]. The Hill coefficient n H E2 obtained from the plot logy/(1 y)=f(log[SO 42 ]) indicates strong positive cooperativity 34 (Fig. 4A). The narrow concentration window in which the transition occurs (Fig. 4A, insert) supports this conclusion. This result is unexpected as the second binding event creates unfavourable electrostatic interactions between the two anions, constrained in close proximity within a single pocket. 35,36 The occurrence of positive cooperativity may be rationalised by considering that the conformational change triggered by the first molecule of sulfate brings all the hydrogen bond donor components of the second binding site (CHs and NHs) in the correct position to bind the second molecule of sulfate, considerably enhancing affinity for the subsequent binding event (K 1 {K 2 ). The electrostatic repulsion between the two anions is presumably offset by both the formation of multiple hydrogen bonds and attractive electrostatic interactions between the anions and the polycationic Solomon link. The affinity of the Solomon link for sulfate, extrapolated from the Hill plot, is highly dependent on temperature. The overall association constant b=K 1 K 2 is weak at 263 K (b= 13 M 2 ) and increases with temperature (b= 6.8 10 3 M 2 at 313 K). Van’t Hoff analysis (Fig. 4B) shows that binding is entropically driven (DS1= +348 10 J mol 1 K 1 ,DH1= +86  4 kJ mol 1 ). The switch can thus be efficiently operated by changing temperature between 263 K and 313 K in the presence of a small excess of SO 42 (2.6 equiv., Fig. 4C). Sulfate-bound conformer 2is favoured at high temperature. The host–guest complex dissociates when the temperature decreases, and the Solomon link switches back to conformer 1. Sulfate-bound conformer 2was only observed in methanol and not in other solvents such as acetonitrile and water (Fig. S21–S22, ESI†), which stabilise better the other conformers. 31 Eventhepresenceofsmallamounts of water in methanol interferes with the formation of the host–guest complex (Fig. S23, ESI†). It is also interesting to note that the transformation 1-2results in a contraction of the Solomon link detectable by both diffusion spectroscopy (DOSY) and ion-mobility mass spectrometry (IM-MS). During the conformational change, an increase in diffusion coefficient indicates a decrease in ca. 30% of the Solomon link bulk volume consistent with the values measured from the molecular models (Fig. S24, ESI†). The contraction is also evidenced by IM-MS. A clear decrease in experimental collision cross-section values measured upon binding of the two equiv. of sulfate confirms that sulfate-bound conformer 2is more compact ( DT CCS He = 395.4 Å 2 for [SL-4H] 4+ vs. 378.8 Å 2 for [SL + 2SO 4 ] 4+ , see Table S2 for details, ESI†). Here again, the experimental DT CCS He measured for [SL + 2SO 4 ] 4+ closely corresponds to the theoretical TMLJ CCS He value of 373.5 Å 2 calculated from the optimized DFT structure. The host–guest complexes formed with other anions are observed with lower abundance and display larger DT CCS He values compared to [SL4H] 4+ , indicating exclusion complexation. The conformational change thus appears to be specific to SO 42 both in solution and in the gas phase. The Solomon link is a remarkably polymorphic molecule, able to undergo either medium (as previously reported) 31 or large amplitude deformations, depending on the experimental conditions. We have now identified three different conformers, whose NMR features are compared in Fig. S25 (ESI†). The protean behaviouroftheSolomonlink,reminiscentofthatofbiomolecules, is considerably more complex than that of topologically simpler macromolecules. Such findings may thus lay the groundwork for the design of increasingly sophisticated entangled macrocycles that can change their three-dimensional shape, and perhaps their function, in response to multiple stimuli. The authors thank the Department of Chemistry at the University of Jyva ¨skyla ¨, the Department of Organic Chemistry at the University of Geneva, the MICIU/AEI of Spain (projects Fig. 3 (A) (+)ESI-MS spectrum of the Solomon link after addition of sulfate (1 : 1 molar ratio, 1 mM each) in CH 3 OH. (B) Representation of the ionmobility mass spectrometry drift times and arrival time distributions at m/z 575 and 624, corresponding to ions [SL-4H] 4+ (in pink) and [SL +2SO 4 ] 4+ (in blue), respectively. Fig. 4 (A) Hill plot obtained from a titration of SO 42 into a CD 3 OD solution of the Solomon link at 313 K. The insert shows the corresponding speciation curve. 34 In this plot, [SO 42 ] is normalized by the apparent equilibrium constant K0corresponding to the concentration of SO 42 producing half-occupation. (B) Van’t Hoff plot. (C) Variable temperature 1 H NMR spectra of the Solomon link after addition of 2.6 equiv. of sulfate (CD 3 OD, 500 MHz). 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