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J Am Chem Soc
J Am Chem Soc
ja
jacsat
Journal of the American Chemical Society
0002-7863
1520-5126
American Chemical Society

39167697
10.1021/jacs.4c05274
Communication
Biomimetic Entropy-Dominant Molecular Hinges with Picomolar Affinity
https://orcid.org/0000-0003-4111-7064
Huang Zehuan †
Groombridge Alexander S. †
Wu Guanglu
Olesińska Magdalena
https://orcid.org/0000-0001-9833-1390
Chen Xiaoyi
McCune Jade A.
https://orcid.org/0000-0001-8032-7166
Scherman Oren A. *
Melville Laboratory for Polymer Synthesis, Yusuf Hamied Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, United Kingdom
E-mail: oas23@cam.ac.uk.
21 08 2024
04 09 2024
146 35 2424424249
17 04 2024
31 07 2024
30 07 2024
© 2024 The Authors. Published by American Chemical Society
2024
The Authors
https://creativecommons.org/licenses/by/4.0/ Permits the broadest form of re-use including for commercial purposes, provided that author attribution and integrity are maintained (https://creativecommons.org/licenses/by/4.0/).

Molecular hinges are ubiquitous in both natural and artificial supramolecular systems. A major challenge to date, however, has been simultaneously achieving high thermodynamic and kinetic stability. Here, we employ host-enhanced intramolecular charge-transfer interactions to mediate entropy-favored complexation between a flexible AB2-type guest and a macrocyclic host, forming a new type of molecular hinge with an ultrahigh picomolar binding affinity (Ka > 1012 M–1). This entropy-promoted hinge modulates photoisomerization, exhibiting a substantial preference for the E-isomer, which is further demonstrated to mirror the natural retinal-opsin cycle, promoting the sensitization of visible light. This work unveils an efficient approach to exploit entropy-dominant architectures for the design of hierarchical molecular systems.

H2020 European Research Council 10.13039/100010663 726470 Engineering and Physical Sciences Research Council 10.13039/501100000266 EP/R512461/1 Engineering and Physical Sciences Research Council 10.13039/501100000266 EP/G037221/1 FP7 People: Marie-Curie Actions 10.13039/100011264 607602 document-id-old-9ja4c05274
document-id-new-14ja4c05274
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pmcMolecular hinges are of great importance in natural1−5 and artificial6−8 self-assembled systems. Natural molecular hinges emerged from structural determination of human immunoglobulin G (1969),1 in which two heavy peptide chains are connected by interchain disulfide bridges. Several strategies have been exploited for the construction of artificial molecular hinges: directional folding through rotation of covalent bonds7 and intramolecular hinging through noncovalent interactions.8 Both suffer from a loss of conformational entropy, resulting in dynamic structures with limited thermodynamic stability.9,10 In natural molecular hinges, this entropy loss can be compensated by additional energy inputs (e.g., ATP and light), resulting in an out-of-equilibrium state, which remains unexplored in artificial molecular hinges. Although significant advances have been made, designing ultrastable, entropy-favored molecular hinges remains a challenge.

On account of their high binding affinity, cucurbit[n]uril (CB[n])-mediated host–guest interactions have been extensively employed in supramolecular oligomers11,12 and polymers,13−17 dynamic hydrogels,18 molecular separators,19 protein/peptide assemblies,20 and other functional systems.21,22 CB[8] reinforces intermolecular π–π,23 polar−π,24,25 and charge-transfer26 interactions (Figure 1a). We envisaged designing intramolecular hinges through CB[8]-mediated complexation, whereby energy gained upon complexation compensates conformational entropic loss.

Figure 1 Schematics of (a) discrete CB[8]-mediated charge-transfer complexation between MV and Np; (b) molecular hinge formed from NpV2 and CB[8]; (c) sequential displacement; and (d) molecular structure of AzoV2 and control over its photoisomerization with CB[8]. Counterions are omitted for clarity.

We employ a macrocyclic host to enhance intramolecular charge-transfer interactions between donor and acceptor motifs (Figure 1b) within a tritopic AB2 guest. Compared to intermolecular complexation (Figure 1a), intramolecular complexation of adjacent donor–acceptor moieties circumvents translational and conformational entropic losses,27−30 offering a driving force for hinge formation. An extra donor–acceptor motif within the AB2 guest provides additional cooperativity, leading to substantial increases in binding affinity for molecular hinges.

As a proof of concept, an AB2 guest (NpV2), bearing two viologen derivatives (blue, electron acceptor) and one naphthyl moiety (orange, electron donor), was prepared (Figure 1b). An equimolar mixture of NpV2 and CB[8] resulted exclusively in a host-induced molecular hinge.100 Ultrahigh binding affinity was demonstrated through sequential competitive replacements, Figure 1c. Typically, 1-adamantylamine (ADA, 109 M–1) readily displaces intermolecular donor–acceptor pairs from CB[8];26 here, the AB2 guest NpV2 replaced ADA, highlighting its ultrahigh affinity (1012 M–1). To demonstrate the use of external energy input for hinge stabilization, another AB2 guest (AzoV2) was prepared (Figure 1d). Complexation of AzoV2 with CB[8] enabled the fabrication of an artificial molecular hinge driven by light, mimicking light-assisted natural hinge systems.

Host-induced molecular hinge formation was studied through 1H NMR titrations, as shown in Figure 2a. Titration of free NpV2 (5.0 mM) into CB[8] (0.1 mM) at a molar ratio of 0.4 resulted in two sets of split peaks from two viologen environments, suggesting a 1:2 pseudostatic complex of NpV2-2CB[8] (Figure 2a). Continued titration to an equimolar ratio (1:1) led to a new series of sharp peaks. Compared to free NpV2, one set of the new viologen peaks (Ha–d) from NpV2-CB[8] exhibited a significant upfield shift, while the other displayed a considerable downfield shift (Ha′–d′). This arises from two distinct viologen environments (bound and unbound) within the 1:1 complex, confirming the formation of the NpV2-CB[8] molecular hinge.

Figure 2 (a) 1H NMR spectra (D2O, 298 K) obtained through titration of NpV2 (5.0 mM) into CB[8] (0.1 mM), in which the proton peaks (a′, b′, c′, d′) refer to the viologen moiety locating outside the intramolecular charge-transfer complex; (b) ITC plot (H2O, 298 K) obtained through titration of NpV2 (1.0 mM) into CB[8] (0.1 mM); and (c) ESI-MS spectra for NpV2-CB[8] (1.0 mM), Np2V-CB[8] (1.0 mM), and AzoV2-CB[8] (1.0 mM). Counterions are omitted for clarity.

Isothermal titration calorimetry (ITC) confirmed stepwise binding; titration of NpV2 into CB[8] led to a binding curve with two clear transitions, Figure 2b. At a molar ratio of 0.5, a 1:2 complex (NpV2-2CB[8]) was formed in the presence of excess CB[8]. Further addition of NpV2 consumed the CB[8] from the weakly bound binary viologen (pseudostatic) complex, resulting in exclusive formation of the 1:1 NpV2-CB[8] species.

Generality of the AB2-CB[8] hinge design was further demonstrated with two additional AB2 guests (Np2V and AzoV2, Figures S2 and S3). Np2V inverted the number of viologen and naphthyl moieties, while AzoV2 replaced the naphthyl donor with a photoresponsive azobenzene. Overcoming typical ITC detection limits (103 M–1 < Ka < 109 M–1) was accomplished through competitive experiments with amantadine (ADA), indirectly yielding binding constants for the AB2-CB[8] hinges (see Figures S45 and S46); all thermodynamic parameters are summarized in Table 1. The AB2-CB[8] hinges exhibited Ka values over 1012 M–1, which unambiguously confirms a general ultrahigh affinity arising from this new design. These new molecular hinges were also observed in high-resolution ESI-MS with mass peaks (Figure 2c–e), consistent with their calculated m/z values.

Table 1 Thermodynamic Data for 1:1 Host–Guest Complexes with CB[8] Obtained through Sequential Competitive ITC

guest	Ka (M–1)	ΔH (kcal mol–1)	TΔS (kcal mol–1)	
NpV2	8.1 × 1012	–15.5 ± 0.2	2.1 ± 0.4	
AzoV2	4.5 × 1012	–14.0 ± 0.1	3.3 ± 0.3	
Np2V	1.0 × 1012	–14.7 ± 0.1	1.6 ± 0.3	
ADA	3.1 × 109	–8.2 ± 0.1	4.8 ± 0.2	
MV	6.7 × 106	–6.0 ± 0.1	3.3 ± 0.2	

Formation of the pseudostatic 1:2 complex and the 1:1 molecular hinge was studied by diffusion-ordered NMR spectroscopy (DOSY). All diffusion coefficients (D) for the hinges exhibited similar values of 2.0 × 10–10 m–2 s–1 (Table 2), smaller than for free guests. This indicated an increase in the size of the molecular hinges compared to their free guest. Further reduction in D values was also observed for the 1:2 complexes of NpV2-2CB[8] and AzoV2-2CB[8] containing an additional CB[8]. These results are consistent with literature reports for discrete CB[8] complexes,31 rather than extended polymeric structures arising from intermolecular binding.14−16

Table 2 Diffusion Coefficients (D) for Free Guests and Their 1:1 and 1:2 Host–Guest Complexes with CB[8] Obtained by DOSY

 	 	D (10–10 m–2 s–1)	
guest	free	+1.0 eq. CB[8]	+2.0 eq. CB[8]	
NpV2	3.0 ± 0.5	2.0 ± 0.3	1.8 ± 0.3	
AzoV2	2.8 ± 0.4	2.0 ± 0.4	1.7 ± 0.2	
Np2V	3.1 ± 0.3	2.0 ± 0.3	-	
CB[8]	2.9 ± 0.3	-	-	

To quantify the role of entropy in the hinge formation, two sets of ITC experiments were performed. Titration of ADA into an intermolecular ternary complex of MV-CB[8]-Np resulted in an endothermic binding curve, Figure 3a. Despite its high enthalpic barrier, the translational entropic penalty of individual MV and Np guests bound within the 1:1:1 CB[8] complex was completely overcome by ADA displacement, resulting in an entropy-dominated process. Subsequent titration of NpV2 into ADA-CB[8] led to an exothermic binding curve, Figure 3b, indicating an enthalpic contribution toward hinge formation.

Figure 3 ITC titration plots (H2O, 298 K) of (a) ADA (0.5 mM) into MV-CB[8]-Np (0.03 mM) and (b) NpV2 (0.3 mM) into ADA-CB[8] (0.03 mM); (c) schematic equilibrium of competitive replacement of discrete MV and Np by NpV2 from CB[8]; 1H NMR spectra (D2O, 298 K) of (d) AzoV2 (1.0 mM) and (e) AzoV2-CB[8] (1.0 mM) obtained upon UV irradiation (λ = 350 nm) for 0, 1, and 4 h followed by subsequent heating at 70 °C for 16 h; (f) plot of percentage of Z-isomers in AzoV2, AzoV2-CB[8], and AzoV2-2CB[8]; (g) mechanism of inhibited photoisomerization.

Entropy and enthalpy changes for displacement of discrete MV and Np guests by NpV2 were determined through an equilibrium calculation based on both titrations. Formation of the AB2-CB[8] hinge is dominated by entropy with a ΔS value of 62.6 cal mol–1 K–1 (Figure 3c). This large entropy gain stems from the covalent linkage within NpV2, circumventing a translational entropic penalty. This confirms the importance of intramolecular interactions in the design and formation of stable AB2-CB[8] hinges. It is also worth noting that our AB2-type intramolecular hinge differs from previous reports on multifunctional enthalpy-driven systems (e.g., A3 or A3 + B2) that preferentially form extended intermolecular structures33,34 as well as entropy-driven systems (e.g., UPy-Napy) that favor formation of cyclic oligomers at low concentrations and linear polymers at high concentrations, limited by a concentration-dependent ring–chain equilibrium.35,36

To probe kinetic stability of AB2-CB[8] hinges, we employed AzoV2 and investigated its photoisomerization,37−42Figure 1d. Controllable photoisomerization of azobenzene within a discrete CB[8] ternary complex has been exploited in the fabrication of photoresponsive supramolecular systems.37,39,41,42 Introduction of an azobenzene-containing guest within the molecular hinge would favor the E-isomer and provide a definitive answer to the long-standing question of whether the E → Z photoisomerization takes place inside the CB[8] cavity or only occurs outside the cavity.

Photoisomerization of free AzoV2 and molecular hinges AzoV2-CB[8] and AzoV2-2CB[8] were monitored through time-dependent 1H NMR experiments after UV irradiation at 350 nm followed by heating at 70 °C. Free AzoV2 exhibits 12% Z-isomer at equilibrium (Figure 3d), which increased to 69% after 4 h UV irradiation. Subsequent heating led to quantitative transformation to the E isomer (Z-isomer <1%). Compared to free AzoV2, the percentage of the Z-isomer within AzoV2-CB[8] only displayed a slight increase from 6% at equilibrium to 9% following 4 h UV irradiation (350 nm), Figure 3e. This indicates a substantial preference for the E-isomer, on account of the pseudostatic AzoV2-CB[8] hinge that limits azobenzene dissociation from CB[8].

Quantitative results for Z/E photoisomerization were obtained from 1H NMR experiments (Figure 3f). Unlike free AzoV2 (black), formation of the Z-isomer was substantially suppressed in the complexed form of AzoV2–CB[8] (red) and AzoV2-2CB[8] (blue) after 4 h of UV irradiation. Therefore, Z/E photoisomerization is significantly inhibited inside a confined nanocavity (Figure 3g), answering the long-standing question: E → Z photoisomerization occurs solely in the free state outside the host cavity.

After elucidating the photoisomerization mechanism within the photoactive hinge, we employed AzoV2-CB[8] to devise a biomimetic supramolecular “retinal-opsin” cycle required for vision, Figure 4a.43,44 Natural retinal undergoes ATP-driven enzymatic chemoisomerization, enabling complexation with an opsin protein. This “retinal-opsin” complex is sensitive to visible light, allowing for photoisomerization back to the original retinal structure and subsequent release of retinal from the opsin protein, ready for the next cycle. Our synthetic system mirrors this cycle;45 both isomerization steps are driven by photoirradiation at different wavelengths, Figure 4b.

Figure 4 Schematics of (a) natural and (b) artificial optical sensitization cycle; (c) 1H NMR spectra (D2O, 298 K) of the biomimetic supramolecular “retinal-opsin” cycle. The concentration (50 μM) is comparable to that of retinal-opsin in the human eye,32 resulting in limited signal/noise ratio.

Figure 4c shows each step of the biomimetic cycle: (i) the AzoV2E-isomer undergoes photoisomerization at 350 nm to form the Z-isomer; (ii) CB[8] complexes with Z-AzoV2 through encapsulation of the azobenzene moiety; (iii) the Z-AzoV2-CB[8] complex undergoes photoisomerization with irradiation at 420 nm visible light to form the E-AzoV2-CB[8] complex (hinge); (iv) memantine(DMADA)-driven decomplexation releases E-AzoV2 from CB[8], ready for the next cycle. 1H NMR confirms quantitative formation of E-AzoV2-CB[8] upon photoirradiation at 420 nm after only 5 min (50 μM, comparable to the concentration of retinal-opsin found in the human eye32). Without CB[8] quantitative photoisomerization to E-AzoV2 does not occur (see Supporting Information Figure S48). Together with the data shown in Figure 3d and Figure 3e, these results show that the presence of CB[8], and formation of the AB2-CB[8] hinges, can significantly alter the ratio of E:Z isomers, allowing access to a quantitative (99%) solution of one isomer of azobenzene through noncovalent chemistries, without altering the chemical structure. This approach unveils a powerful route to selectively access isomers in ratios outside the photostationary state using reversible supramolecular chemistry.

Notably, the complexation of trans retinal with opsin is dominated by an entropic gain (ΔS = 34.6 cal mol–1 K–1, ΔH ≈ 0 kcal mol–1),46 similar to formation of the AB2-CB[8] hinge (ΔS = 62.6 cal mol–1 K–1, ΔH = 3.1 kcal mol–1), Figure 3c. Such a high affinity of the entropy-favored E-AzoV2-CB[8] complex leads to host-promoted isomerization, significantly lowering the overall free energy of the system. Both natural and artificial cycles contain four distinct steps, are sensitive to light and rely upon a single external chemical energy input (ATP & DMADA) ensuring cycle continuity. All the above highlights that AzoV2-CB[8] acts as a biomimetic supramolecular equivalent of the natural “retinal-opsin” complex, demonstrating an example of the artificial optical sensitization cycle.

In conclusion, we designed a new molecular hinge through host-enhanced charge-transfer interactions between a flexible, tritopic guest and a CB[8] macrocycle. Through entropy-dominant self-assembly, these molecular hinges possess picomolar binding with Ka > 1012 M–1, exhibiting ultrahigh thermodynamic affinity. Binding within the molecular hinge also displays high kinetic stability, inhibiting E → Z photoisomerization of azobenzene with a significant preference for the E-isomer and a relative ratio of E/Z over 1 order of magnitude. Furthermore, our supramolecular system driven by multistep processes mirrors that of the natural retinal-opsin cycle (4 steps, mediated by light, molecular recognition, and a single chemical input). This work introduces a general entropy-dominant approach to exploit ultrastable molecular hinges as a functional handle toward the design of molecular machines, artificial nanorobots, and biomimetic systems.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacs.4c05274.Instrumentation, synthesis of AB2-type guests, 1H and 2D NMR spectra for host–guest complexes, UV–vis spectra for photoisomerization, ITC titration plots and fitted curves (PDF)

Supplementary Material

ja4c05274_si_001.pdf

Author Contributions

† Z.H. and A.S.G. contributed equally to this work.

The authors declare no competing financial interest.

Acknowledgments

O.A.S. and Z.H. thank ERC Consolidator Grant CAM-RIG (726470). A.S.G acknowledges NanoDTC program (EP/G037221/1). M.O. thanks Marie Curie FP7 SASSYPOL ITN (607602). X.C. acknowledges CDT and EPSRC Grant (EP/R512461/1).
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