A supramolecular approach to metal ion sensing: cystine-based designer systems for Cu²⁺, Hg²⁺, Cd²⁺ and Pb²⁺ sensing

Abstract

We have synthesized two cystine containing molecules S1 (pyrene-labelled) and S2 (tryptophan-labelled) and demonstrated that the former can detect Cu²⁺, and the latter can detect Hg²⁺ in acetonitrile. The 1 : 1 mixture of S1 and S2 forms a heterodimeric system S1 : S2, which was confirmed by mass spectrometric, UV-Visible and fluorescence spectroscopic studies. Additional proof for the formation of S1 : S2 came from ¹H NMR, CD, ITC, ultramicroscopic and computational studies. The supramolecularly assembled S1 : S2 detects Pb²⁺ in nanomolar levels. A control compound S3 containing tryptophan and pyrene units showed totally different binding properties compared to S1, S2 and S1 : S2. DFT studies on S1 : S2 establish that S1 in S1 : S2 adopts an extended conformation, thereby keeping the pyrene units proximal to the indole moiety of S2 for energy transfer. The binding of Pb²⁺ with S1 : S2 brings the two pyrene units into proximity resulting in a folded structure and the formation of the excimer. These results clearly demonstrate a hitherto unknown and unexpected organization of two fluorescent molecules leading to a new supramolecular system capable of Pb²⁺ detection.

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Introduction

Molecular structure is the key to functional properties and this notion spearheaded the design and synthesis of a wide variety of molecules with unusual architectures.¹ Chemical synthesis, therefore became a powerful discipline because it can create new molecular entities. The last few decades of developments in chemistry have shown that the association of molecules through non-covalent interactions leads to intricate molecular assemblies. Such supramolecular assemblies are capable of exhibiting new emergent properties.² The emergent property is a higher level property, which cannot be predicted from the properties of constituent entities.³ The emergent behaviour of a collection of molecules is more than the sum of the behaviors of its parts. Under this rubric, chemists have attempted to design and synthesize a variety of chemical systems that demonstrate emergent properties such as the self-replicating property,⁴ supramolecular chirality,⁵ and chirality transfer.⁶

The control and predictability of the non-covalent interactions are the challenges for the design of functional materials with emergent properties.⁷ Conjugating a well known hydrogen bonding motif such as melamine or diketopiperazine to a molecule of interest for achieving desired supramolecular assembly is an approach used by chemists.⁸ Herein, we report a hitherto unknown and unexpected organization of two fluorescent molecules based on cystine. In the present study, we chose cystine as a basic structure for the design since, the S–S bond in cystine could serve as potential metal ion binding site.⁹ In addition to that, N and C-termini of cystine can be easily functionalizable with a variety of metal ion binding motifs or by fluorescent probes or both. The other reason being, orthogonality of S–S bond provides a kink and can induce a turn architecture, such a preorganization could further facilitate the metal ion binding.

Results and discussion

The synthesized cystine-based molecules S1–S3 are given in Fig. 1. Due to the orthogonality of disulfide linkage in S1 and S2, the appended fluorophores could align closely (conformer 1, Fig. 1) or they could be far apart (conformer 2, Fig. 1). In S1, pyrene is chosen as a fluorescent probe owing to its distinctive monomer and excimer emissions coupled with high detection sensibility. In addition to these, the emission wavelength of pyrene is sensitive to the polarity of the local environment.¹⁰ In the case of S2, tryptophan is the fluorophore and the molecule can be described as a completely peptidic system. The choice of Trp was primarily due to its fluorescence and the metal ion binding capability of its indole ring. In fact, Trp plays a fundamental role in many important metal ion binding proteins. For example, EF-hand motif and in CusF protein, indole ring of Trp binds to Ca²⁺ and Cu²⁺ respectively through cation–π interaction.¹¹

Fig. 1 (a) Structures of cystine-based sensors used in the study (b) conformational equilibrium of S1.

For the synthesis of S1, the C-termini of Boc-cystine were functionalized with pyrene, by coupling pyrene methylamine to bis-Boc-cystine using dicyclohexylcarbodiimide (DCC) and N-hydroxysuccinimide (NHS). Similarly, S2 was synthesized from Boc-cystine and TrpOMe.

S1 on excitation at 340 nm shows two closely spaced emission bands at 380 nm and 390 nm with a broad band at 480 nm (Fig. 2a). The bands at 380 and 390 nm attribute to monomer emission and the 480 nm is due to the excimer emission. The I₄₈₀/I₃₈₀ values measured over a range of concentrations indicate that the excimer was independent of concentration (Fig. S1a in ESI†).¹² The excitation spectra of S1 recorded at 380 nm and 480 nm in acetonitrile was different suggesting the formation of a ground state intramolecular pyrene dimer (Fig. S2a in ESI†).¹³

Fig. 2 (a) Fluorescence spectra of S1 [10 μM] in acetonitrile with and without addition of Cu(ClO₄)₂, λ_ex = 340 nm (b) fluorescence spectra of S2 [15 μM] in acetonitrile with and without addition of Hg(ClO₄)₂, λ_ex = 290 nm (c) fluorescence spectra of S3 [12 μM] in acetonitrile with and without addition of Cd(ClO₄)₂, λ_ex = 290 nm (d) CD spectrum of S1 [500 μM] in acetonitrile (e) CD spectrum of S2 [500 μM] in acetonitrile (f) CD spectrum of S3 [500 μM] in acetonitrile.

The metal ion binding ability of S1 in CH₃CN was studied by fluorescence spectroscopy. The order of metal ion binding was found to be Cu²⁺ > Hg²⁺ > Fe³⁺ > Ag⁺ > Cs⁺ ∼ Mg²⁺ ∼ Ba²⁺ ∼ Pb²⁺ ∼ Mn²⁺ ∼ Co²⁺ > Zn²⁺ > Cd²⁺ > Na⁺ > K⁺ (Fig. S3a in ESI†). The fluorescence quenching was higher for Cu²⁺ and Hg²⁺ compared to other metal ions tested. The Stern–Volmer quenching constant (K_sv) of S1 with Cu²⁺ was found to be 6 × 10⁵ M⁻¹ (Fig. S4a in ESI†) with a detection limit of 0.6 μM. The competitive binding experiments revealed that S1 can detect Cu²⁺ even in the presence of higher concentrations of other metal ions (Fig. S5a in ESI†). The time-resolved fluorescence spectroscopic studies showed that the fluorescence lifetime of S1 decreases upon adding Cu²⁺. The ratio of fluorescence intensity of S1 using a steady-state fluorescence studies was found to be equal to the ratio of decay time (F₀/F = τ₀/τ), (where τ₀ and F₀ are the fluorescence lifetime and intensity in the absence of Cu²⁺, τ and F are the fluorescence lifetime and intensity in the presence of Cu²⁺) indicating a dynamic quenching mechanism (Fig. S6 and Table S2 in ESI†).¹⁴ The circular dichroism (CD) spectrum of S1 revealed a maximum at 213 nm and minimum at 206 nm with a crossover at 211 nm (Fig. 2d) indicating a turn-like conformation.¹⁵ The addition of Cu²⁺ to S1 resulted in very small changes in the CD signal intensity (Fig. S7a in ESI†) implying no significant conformational changes upon binding. The stoichiometry of S1–Cu²⁺ complex was found to be 1 : 1 by Job's plot (Fig. S8a in ESI†).

The binding studies of S2 with various metal ions showed that it exhibits a high binding affinity for Hg²⁺ followed by Cu²⁺ (Fig. S3b in ESI†). The selectivity of S2 for metal ions is in the order Hg²⁺ > Cu²⁺ > Ag⁺ > Ba²⁺ > Cs⁺ > Fe³⁺ ∼ Pb²⁺ > Na⁺ > Co²⁺ ∼ Zn²⁺ > Sn²⁺ > K⁺ ∼ Mg²⁺ ∼ Cd²⁺ ∼ Mn²⁺ (Fig. S5 in ESI†). The fluorescence band at 330 nm was quenched by the addition of Hg²⁺ to a solution of S2 in acetonitrile. The stoichiometry of the S2–Hg²⁺ complex was found to be 1 : 1 by Job's plot (Fig. S8b in ESI†). S2 displayed a color change from colorless to orange brown upon binding to Cu²⁺ (Fig. S9a in ESI†), and this visible colorimetric response was not observed with other metal ions. The involvement of Trp side chain for binding Hg²⁺ was confirmed by the ¹³C NMR spectrum.¹⁶ Considerable downfield shifts in the ¹³C NMR for the –S–CH₂–carbon atoms (0.91 ppm) and amide carbonyls (0.48 ppm) indicates that Hg²⁺ binds to –S–S– atoms and amide carbonyls. The aromatic carbon atoms also showed a downfield shift of 0.2 ppm indicating the involvement of aromatic moieties in Hg²⁺ binding (Fig. S10 and Table S1 in ESI†). The interference of the potentially competing metal ions on Hg²⁺ detection has also been investigated in the presence of other metal ions and the results demonstrate that S2 is very selective to Hg²⁺ (Fig. S5b in ESI†). S2 showed a binding constant of 3.3 × 10³ M⁻¹ (Fig. S4b in ESI†) and a detection limit of 1.5 μM.

The time-resolved fluorescence measurements showed that the quenching observed in the S2 with Hg²⁺ is static type (Table S3 and Fig. S11b in ESI†), since there is no change in the fluorescence decay time for S2 even after the addition of 3 equiv. of Hg²⁺.¹⁴ The CD spectrum of S2 revealed a minimum at 215 nm and a maximum at 225 nm with a cross over point at 221 nm supportive of a turn-like conformation (Fig. 2e).¹⁵ The CD spectrum remains the same after the addition of 10 equiv. of Hg²⁺ indicating no conformational change in S2 upon complexation with Hg²⁺ (Fig. S7b in ESI†).

The two fluorophores (pyrene and Trp) can form fluorescence resonance energy transfer (FRET) pair, as the absorption spectrum of pyrene overlaps with the emission spectrum of tryptophan.¹⁷ We envisioned that an asymmetric system equipped with probes capable of forming FRET will widen the versatility of our system. With this in mind, we performed disulfide exchange reaction by reacting S1 and S2 under reducing condition and further oxidation produced disulfide shuffled product S3 (Fig. 1). Excitation of S3 at 290 nm gives an emission band at 335 nm that corresponds to the tryptophan emission band with low intensity excimer band of pyrene at 470 nm, this observation indicates FRET. When S3 is titrated with Cd²⁺ ion, there is an increase in the intensity of emission bands at 335 and 470 nm (Fig. 2c); indicates that Cd²⁺ binding enhances FRET between Trp and pyrene. Time-resolved fluorescence measurements showed that the decay time (τ) of Trp in S3 decreased in comparison to the decay time of S2 (Tables S3 and S4 in ESI†), this indicating that the energy transfer mechanism is by FRET between donor Trp and acceptor pyrene. The fluorescence decay time of Trp further decreased upon the addition of Cd²⁺ ion indicating an enhanced FRET upon complexation. Excimer formation upon Cd²⁺ binding (Fig. S2c in ESI†) supported intermolecular dimerization and the Job's plot clearly revealed a 2 : 1 stoichiometry for S3 and Cd²⁺ (Fig. S8e in ESI†). The binding constant was found to be 2.2 × 10⁶ M⁻² with a detection limit of 2 μM. Mass spectrometric data confirmed a Cd²⁺ bound intermolecular dimer at m/z 1821.5470 (S3 + Cd²⁺ + H⁺) (Fig. S12a in ESI†). S3 displayed a color change from colorless to yellow upon the addition of Cd²⁺ indicating that S3 can acts as a visual detector for Cd²⁺ (Fig. S9b in ESI†). The CD spectrum revealed only intensity changes in the CD signal after the addition of Cd²⁺, signifying no conformational change in S3 as a result of Cd²⁺ complexation (Fig. S7c in ESI†).

Computational studies using density functional theory (DFT) supported a dimeric structure with Cd²⁺ in octahedral geometry (Fig. S13d in ESI†). Only one of the sulphur from each disulfide bond is coordinated to the metal. Average Cd–O distance is 2.28 Å. One of the pyrene units comes in the vicinity of the indole moiety closest C(pyrene)–C(indole) ring distance is 4.08 Å, thus supporting the observed FRET.

Since pyrene and Trp can form a FRET pair, we envisioned that a supramolecular assembly of S1 and S2 may lead to an intermolecular FRET and possibility for an emergent property. In fact, a 1 : 1 mixture of S1 and S2 namely S1 : S2 in acetonitrile displayed a very different absorption spectrum compared to the summed absorption spectra of S1 and S2 indicative of intermolecular heterodimeric supramolecular interactions (Fig. S14a in ESI†). The UV spectrum of S1 : S2 is characterized by a drastic redshift of 15 nm compared to the UV spectra of S1 and S2 (Fig. S14b in ESI†). Similarly, the emission spectrum of S1 : S2 (λ_ex = 290 nm) showed an excimer at 470 nm, while the excimer in S1 was found to be at 480 nm. ¹H-NMR spectrum of an equimolar mixture of S1 and S2 in CD₃CN displayed, a downfield shift of amide NHs (a, d, f, and i) (0.3 ppm) and indole NH (j) (0.2 ppm) supporting the formation of supramolecular complex S1 : S2 by non-covalent interactions (Fig. S15a in ESI†). The mass spectrometric analysis of S1 : S2 showed m/z 1706.6360, which supports the formation of a heteromeric dimer (Fig. S12b in ESI†). The titration of S1 and S2 was monitored UV spectroscopically and the Job's plot showed a 1 : 1 complexation (Fig. S8c in ESI†).

The fluorescence spectrum of S1 : S2 (λ_ex = 290 nm) showed a band at 470 nm indicating the energy transfer from Trp to pyrene. These results support the formation of a heterodimeric structure for S1 : S2 in which pyrene moiety of S1 and indole unit of S2 are in proximity for exhibiting FRET. In order to confirm the formation of a FRET pair, we performed lifetime measurements on individual compounds and the mixture. The fluorescence lifetime of donor (Trp) decreased from 1.01 ns (in S2) to 0.48 ns in S1 : S2 which clearly indicates resonance energy transfer (Table S5 in ESI†).¹⁴ The CD spectrum of the S1 : S2 in acetonitrile revealed a minimum at 234 nm and a maximum at 214 nm, with a crossover at 220 nm (Fig. 3e). The different CD spectrum of S1 : S2 compared to that of S1 and S2 indicates conformational changes and supports the formation of supramolecular structure (Fig. 3e).

Fig. 3 Optimized structures of (a) the heterodimer S1 : S2 (b) HOMO–LUMO orbital diagram for S1 : S2 heterodimer using B3LYP/6-31G* DFT method. The HOMO orbitals are on the indole units, while LUMO orbitals are on pyrene units. An energy gap of −3.68 eV supports the observed FRET in S1 : S2 (c) SEM images of (a) S1 (b) S2 (c) S3 (d) S1 : S2 in acetonitrile (d) ITC titration data of S1 [200 μM] upon titrating against S2 [50 μM]; (n = 1.01, K_a = 3.2 × 10³ M⁻¹). Titrations were performed at 25 °C in acetonitrile and each titration was composed of 25 successive injections of 1 μL of S2. Upper graphs represent experimental data and lower panels represents the binding isotherm obtained by plotting the integrated heats from each injection against the molar ratio of the compounds (e) CD spectrum of S1 : S2 [500 μM] in acetonitrile.

Theoretical supports to the experimental findings have been obtained from DFT studies using B3LYP/6-31G* method on S1, S2 and S1 : S2. These studies showed that the conformation of S1 changed from a folded (conformer 1) to an extended (conformer 2) upon the formation of the heterodimer S1 : S2 supporting the fluorescence spectroscopic results on S1, S2 and S1 : S2 (Fig. 3a and S13 in ESI†). For instance, the pyrene excimer intensity of S1 decreased significantly upon subsequent addition of S2 suggesting that the pyrene units in S1 are distant in S1 : S2 compared to S1 alone. This fact is clearly captured in the computed structure of S1 : S2. The nearly C2 symmetric heterodimer is stabilized by three pairs of hydrogen bonds between indole NH and pyrene O=C (1.92 Å); Boc O=C of S2 with Boc NH of S1 (1.99 Å); Boc O=C of S1 with amide. NH of S1 (1.97 Å) and the overall stabilization is found to be 16.6 kcal mol⁻¹ (Fig. 3a). The calculations showed that the donor indole and acceptor pyrene moieties are at an average distance of 10 Å, facilitating FRET pair (Fig. 3a). The HOMO orbitals are located on the indole units of S2, whereas LUMO is concentrated on pyrene moieties of S1 with a HOMO–LUMO gap of 3.68 eV (Fig. 3b). Hence, FRET can be attributed mainly due to the transfer of electron density from indole unit of Trp to pyrene moiety.

Clear evidence for the supramolecular nature of the binding interaction between S1 and S2 is obtained from isothermal calorimetric (ITC) titration studies. The ITC studies (Fig. 3d and S16a in ESI†) confirmed that the interaction between S1 and S2 is an entropy-driven endothermic process¹⁸ because the change in enthalpy (ΔH) of 48.9 cal mol⁻¹ and a change in entropy (TΔS) of 4.83 kcal mol⁻¹ resulted in a favourable change in free energy (ΔG) −4.7 kcal mol⁻¹. The calculated binding constant was 3.2 × 10³ M⁻¹ with a stoichiometry of 1 : 1. The observed 1 : 1 stoichiometry is supported by mass spectrometric analysis (Fig. S12b in ESI†). Further, direct evidence for the supramolecular interaction in S1 : S2 complex is obtained from their morphological studies using scanning electron microscopy (SEM). S1 showed a cotton candy-like morphology, whereas S2 showed vesicles with diameters in the range of 610–980 nm. The morphology of S1 : S2 showed no resemblance to the morphology of S1 or S2. The morphological difference observed for S1 : S2 compared to S1 and S2 supports the supramolecular interactions between S1 and S2 (Fig. 3d).

The differential scanning calorimetry (DSC) revealed a sharp melting transition at 177.32 °C and 134.98 °C for S1 and S2, respectively. The S1 : S2 showed an endothermic phase transition at 114.31 °C corresponding to the melting point. The different and distinct thermal transition value of S1 : S2 from either of the individual components signifies the formation of a new molecular entity (Fig. S17 in ESI†).

The DFT optimized geometry of S1 : S2, revealed a heterodimeric structure. We envisioned that the heterodimer S1 : S2 with two disulfide linkages has the potential to bind compatible metal ions. The binding studies of S1 : S2 showed that it has a high binding affinity towards Pb²⁺ (Fig. S3d in ESI†). The competitive binding experiments further revealed that S1 : S2 can detect Pb²⁺ even in the presence of higher concentrations of other metal ions (Fig. S5d in ESI†). This is an emergent property due to assembly, because S1 alone can sense only Cu²⁺, while S2 alone can sense only Hg²⁺ (Fig. S3 in ESI†). The S1 : S2 display a fluorescence “turn-on”, behavior upon binding to Pb²⁺. It also offers a ‘naked-eye’ detection of Pb²⁺ as the color of S1 : S2 solution changed from colorless to green after the addition of Pb²⁺ under UV light (Fig. 4a). The Pb²⁺ binding facilitated excimer formation, as evident from the enhancement in intensity of band at 470 nm (Fig. 4b), supporting the close proximity of pyrene–Trp and pyrene–pyrene moieties. Job's plot and mass spectrometric studies revealed a 1 : 1 stoichiometry (Fig. S8d and 12c in ESI†) for the lead complex. Time-resolved fluorescence spectroscopic studies of Pb²⁺ complex of S1 : S2 showed a decrease in the lifetime of the donor with an enhancement in FRET efficiency (Table S6 in ESI†), suggesting that the distance between pyrene and tryptophan decreases as a result of the complexation.¹⁹ The detection limit of S1 : S2 for Pb²⁺ is found to be 2.4 nM with a binding constant of 6.2 × 10⁴ M⁻¹ (Fig. S4 in ESI†). The ¹H NMR titration (Fig. S15b in ESI†) of S1 : S2 with Pb²⁺ displayed upfield shift for indole NHs (j) and aromatic protons (e + k + l + m + n) presumably as a result of the steric crowding between the indole and the pyrene moieties. The absence of any downfield shift of indole protons strongly suggests that Trp is not taking part in the complexation. The DFT calculations showed that binding of Pb²⁺ to sulfur atoms results in more compact structure of the dimer (Fig. 4c). The CD studies revealed only changes in the signal intensity indicating no major conformational changes upon Pb²⁺ binding (Fig. S7d in ESI†).

Fig. 4 (a) Observed color change under UV light upon binding of S1 : S2 [10 μM] with Pb²⁺ (b) fluorescence spectra of S1 : S2 (1.1 × 10⁻⁵ M) in acetonitrile with and without addition of Pb(ClO₄)₂, λ_ex = 290 nm (c) optimized structure of the heterodimer with Pb²⁺.

Energy minimized structure of S1 : S2 with Pb²⁺ by using B3LYP/6-31G* indicated that the four sulfur atoms bind to metal ion with an average –S–Pb²⁺– distance of 2.9 Å to form a distorted square planar complex (Fig. 4c). The extended conformation (conformer 2) of S1 changes to folded conformation (conformer 1) when Pb²⁺ binds to S1 : S2. In S1 : S2, the distance between the sulfur atoms of S1 and S2 is ∼6.3 Å which got compressed to 4.2 Å as a result of binding with Pb²⁺ (Fig. 4c). The Pb²⁺ binding leads to significant reduction in the indole–pyrene and pyrene–pyrene distances facilitating FRET, and excimer formation.

Conclusion

In conclusion, we report three cystine-based systems S1, S2 and S3 for the selective detection of Cu²⁺, Hg²⁺ and Cd²⁺ ions. We also demonstrated the supramolecular system S1 : S2 formed from S1 and S2 can selectively detect the Pb²⁺ by fluorescence ‘turn on’ behavior through a FRET mechanism. The formation of S1 : S2 was supported by UV, CD, ITC, SEM, DSC and by mass spectrometric methods. The experimental observations were rationalized by DFT studies. The emergent property of S1 : S2 to bind Pb²⁺ is a noteworthy finding. The demonstrated cystine-based systems open up strategies for the construction of novel supramolecular systems for various sensing applications.

Acknowledgements

We thank the Department of Science and Technology (DST and DST-FIST) for financial support and PPPK thanks the University Grants Commission (UGC), New Delhi for the fellowship.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Experimental details for synthesis of S1, S2 and S3, absorption and fluorescence spectra, HRMS, ¹H and ¹³C NMR spectra. ITC and DFT calculations for S1 : S2. See DOI: 10.1039/c4ra14389b

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