Variational Implicit-Solvent Modeling of Host-Guest Binding: A Case Study on Cucurbituril|
ABSTRACT: The synthetic host cucurbituril (CB) binds aromatic guests or metal complexes with ultrahigh affinity compared with that typically displayed in protein-ligand binding. Due to its small size, CB serves as an ideal receptor-ligand system for developing computational methods for molecular recognition. Here, we apply the recently developed variational implicit-solvent model (VISM), numerically evaluated by the level-set method, to study hydration effects in the high-affinity binding of the B2 bicyclo[2.2.2]octane derivative to CB. For the unbound host, we find that the host cavity favors the hydrated state over the dry state due to electrostatic effects. For the guest binding, we find reasonable agreement to experimental binding affinities. Dissection of the individual VISM free-energy contributions shows that the major driving forces are water-mediated hydrophobic interactions and the intrinsic (vacuum) host-guest van der Waals interactions. These findings are in line with recent experiments and molecular dynamics simulations with explicit solvent. It is expected that the level-set VISM, with further refinement on the electrostatic descriptions, can efficiently predict molecular binding and recognition in a wide range of future applications.
Project description:We incorporate the Poisson-Boltzmann (PB) theory of electrostatics into our variational implicit-solvent model (VISM) for the solvation of charged molecules in an aqueous solvent. In order to numerically relax the VISM free-energy functional by our level-set method, we develop highly accurate methods for solving the dielectric PB equation and for computing the dielectric boundary force. We also apply our VISM-PB theory to analyze the solvent potentials of mean force and the effect of charges on the hydrophobic hydration for some selected molecular systems. These include some single ions, two charged particles, two charged plates, and the host-guest system Cucurbituril and Bicyclo[2.2.2]octane. Our computational results show that VISM with PB theory can capture well the sensitive response of capillary evaporation to the charge in hydrophobic confinement and the polymodal hydration behavior and can provide accurate estimates of binding affinity of the host-guest system. We finally discuss several issues for further improvement of VISM.
Project description:Recognition tunneling technique owns the capability for investigating and characterizing molecules at single molecule level. Here, we investigated the conductance value of cucurbituril (CB) and melphalan@CB (Mel@CB) complex molecular junctions by using recognition tunneling technique. The conductances of CB and Mel@CB with different pH values were studied in aqueous media as well as organic solvent. Both pH value and guest molecule have an impact on the conductance of CB molecular junction. The conductances of CB and Mel@CB both showed slightly difference on the conductance under different measurement systems. This work extends the molecular conductance measurement to aqueous media and provides new insights of pH-responsive host-guest system for single molecule detection through electrical measurements.
Project description:Two acyclic CB[n]-type hosts (1 and 2) which possess four 2° or 3° amide arms are reported; 1 and 2 are slightly soluble in water and do not self-associate. Host 2 has four 3° amide arms that exist as a mixture of E- and Z-isomers. 1H NMR was used to qualitatively investigate the binding properties of 1 and 2 which indicates they retain the essential binding features of macrocyclic CB[n] hosts (e.g. cavity binding of hydrophobic residues and portal binding of cationic groups). We measured the Ka values of 1 and 2 toward guests 6 – 12, methamphetamine, and fentanyl by ITC to evaluate their potential as in vivo sequestration agents. Neutral hosts 1 and 2 bind less tightly than tetraanionic hosts M1, ACB1, and ACB2. We attribute the lower Ka values to the absence of secondary ion-ion (ammonium•••sulfonate or ammonium•••carboxylate) electrostatic interactions for host•guest complexes of 1 and 2. The secondary amide functionality on 1 decreases affinity by formation of intramolecular NH•••O=C H-bonds. Tertiary amide host 2 binds even more weakly than 1 due to backfolding of the amide N-CH3-groups of 2 into its own cavity. The x-ray crystal structure of 2 supports this conclusion. Graphical abstract
Project description:Conspectus This Account focuses on stimuli responsive systems that function in aqueous solution using examples drawn from the work of the Isaacs group using cucurbit[n]uril (CB[n]) molecular containers as key recognition elements. Our entry into the area of stimuli responsive systems began with the preparation of glycoluril derived molecular clips that efficiently distinguish between self and nonself by H-bonds and π-π interactions even within complex mixtures and therefore undergo self-sorting. We concluded that the selectivity of a wide variety of H-bonded supramolecular assemblies was higher than previously appreciated and that self-sorting is not exceptional behavior. This lead us to examine self-sorting within the context of CB[n] host-guest chemistry in water. We discovered that CB[n] homologues (CB and CB) display remarkably high binding affinity (Ka up to 10(17) M(-1)) and selectivity (ΔΔG) toward their guests, which renders CB[n]s prime components for the construction of stimuli responsive host-guest systems. The CB·adamantaneammonium ion complex, which is particularly privileged (Ka = 4.2 × 10(12) M(-1)), was introduced by us as a stimulus to trigger constitutional changes in multicomponent self-sorting systems. For example, we describe how the free energy associated with the formation of host-guest complexes of CB[n]-type receptors can drive conformational changes of included guests like triazene-arylene foldamers and cationic calixarenes, as well as induced conformational changes (e.g., ammonium guest size dependent homotropic allostery, metal ion triggered folding, and heterochiral dimerization) of the hosts themselves. Many guests display large pKa shifts within their CB[n]-guest complexes, which we used to promote pH controlled guest swapping and thermal trans-to-cis isomerization of azobenzene derivatives. We also used the high affinity and selectivity of CB toward its guests to outcompete an enzyme (bovine carbonic anhydrase) for a two-faced inhibitor, which allowed stimuli responsive regulation of enzymatic activity. These results prompted us to examine the use of CB[n]-type receptors in both in vitro and in vivo biological systems. We demonstrated that adamantaneammonium ion can be used to intracellularly sequester CB from gold nanoparticles passivated with hexanediammonium ion·CB complexes and thereby trigger cytotoxicity. CB derivatives bearing a biotin targeting group enhance the cytotoxicity of encapsulated oxaliplatin toward L1210FR cells. Finally, acyclic CB[n]-type receptors function as solubilizing excipients for insoluble drugs for drug delivery purposes and as a broad spectrum reversal agent for the neuromuscular blocking agents rocuronium, vecuronium, and cis-atracurium in rats. The work highlights the great potential for integration of CB[n]-type receptors with biological systems.
Project description:The binding of imidazolium salts to cucurbituril, CB, triggers a stepwise self-assembly process with semiflexible polymer chains and crystalline nanostructures as early- and late-stage species, respectively. In such a process, which involves the crystallization of the host-guest complexes, the guest plays a critical role in directing self-assembly toward desirable morphologies. These include platelet-like aggregates and two-dimensional (2D) fibers, which, moreover, exhibit viscoelastic and lyotropic properties. Our observations provide a deeper understanding of the self-assembly of CB complexes, with fundamental implications in the design of functional 2D systems and crystalline materials.
Project description:Host-guest interactions between a synthetic receptor, cucurbituril (CB), and gold nanoparticles (AuNPs) have been quantified using isothermal titration calorimetry. AuNPs were functionalized with ligands containing tertiary or quaternary benzylamine derivatives, with electron donating or withdrawing groups at the para position of the benzene ring. Analysis of binding interactions reveals that functional groups at the para position have no significant effect on binding constant. However, headgroups bearing a permanent positive charge increased the binding of AuNPs to CB ten-fold compared to monomethyl counterparts.
Project description:A photoswitchable arylazopyrazole (AAP) derivative binds with cucurbituril (CB) and methylviologen (MV2+ ) to form a 1:1:1 heteroternary host-guest complex with a binding constant of Ka =2×103 ?m-1 . The excellent photoswitching properties of AAP are preserved in the inclusion complex. Irradiation with light of a wavelength of 365 and 520?nm leads to quantitative E- to Z- isomerization and vice versa, respectively. Formation of the Z-isomer leads to dissociation of the complex as evidenced using 1 H?NMR spectroscopy. AAP derivatives are then used to immobilize bioactive molecules and photorelease them on demand. When Arg-Gly-Asp-AAP (AAP-RGD) peptides are attached to surface bound CB/MV2+ complexes, cells adhere and can be released upon irradiation. The heteroternary host-guest system offers highly reversible binding properties due to efficient photoswitching and these properties are attractive for designing smart surfaces.
Project description:Long-lived organic room-temperature phosphorescence (RTP) has received great attention because of its various potential applications. Herein, we report a persistent RTP of a solid-state supramolecule between a cucurbituril (CB) host and a heavy-atom-free phenylmethylpyridinium guest. Significantly, the long-lived phosphorescence completely depends on the host-guest complexation, revealing that the non-phosphorescent guest exhibits a 2.62 s ultralong lifetime after being complexed by CB under ambient conditions. The ultralong RTP is because of tight encapsulation of CB, which boosts intersystem crossing, suppresses nonradiative relaxation and possibly shields quenchers. Moreover, several phosphorescent complexes possessing different lifetimes are prepared and successfully applied in triple lifetime-encoding for data encryption and anti-counterfeiting. This strategy provides a new insight for realizing purely organic RTP with ultralong lifetime and expands its application in the field of information protection.
Project description:Sub-micrometer/nanoscale patterned polymer brushes are prepared by employing cucurbituril (CB) as a supramolecular recognition motif to assemble functional silica colloids onto Au surfaces as a sacrificial nanopatterning template. By employing CB-mediated host-guest interactions at the interface, it is possible to readily generate nanopatterned materials in aqueous media under ambient conditions.
Project description:Recent efforts to develop hydrogel biomaterials have focused on better recapitulating the dynamic properties of the native extracellular matrix. In hydrogel biomaterials, binding thermodynamics and cross-link kinetics directly affect numerous bulk dynamic properties such as strength, stress relaxation, and material clearance. However, despite the broad range of bulk dynamic properties observed in biological tissues, present strategies to incorporate dynamic linkages in cell-encapsulating hydrogels rely on a relatively small number of dynamic covalent chemical reactions and host-guest interactions. To expand this toolkit, we report the preparation of supramolecular gelatin hydrogels with cucurbituril (CB)-based cross-links that form on demand via thiol-ene reactions between preassembled CB·FGGC peptide ternary complexes and grafted norbornenes. Human fibroblast cells encapsulated within these optically transparent, shear thinning, injectable hydrogels remained highly viable and exhibited a well-spread morphology in culture. These CB-based gelatin hydrogels are anticipated to be useful in applications ranging from bioprinting to cell and drug delivery.