Entropy Effects in Intermolecular Associations of Crown-Ethers and Cyclodextrins with Amino Acids in Aqueous and in Non-Aqueous Media

The analysis of the ratios of entropy and enthalpy characteristics and their contributions to the change in the Gibbs energy of intermolecular interactions of crown ethers and cyclodextrins with amino acids is carried out. Two different types of macrocycles were chosen for examination: crown ethers with a hydrophilic interior and cyclodextrins with a hydrophobic inner cavity and a hydrophilic exterior. The thermodynamics of complex formation of crown ethers and cyclodextrins with amino acids in water and aqueous-organic solvents of variable composition was examined. The contributions of the entropy solvation of complexes of 18-crown-6 with glycine, alanine, phenylalanine to the change in the entropy of complexation in water-ethanol and water-dimethyl sulfoxide solvents was calculated and analyzed. It was found that the ratios of the entropy and enthalpy solvation of the reagents for these systems have similar trends when moving from water to aqueous-organic mixtures. The relationship between the thermodynamic characteristics and structural features of the complexation processes between cyclodextrins and amino acids has been established. The thermodynamic enthalpy–entropy compensation effect was revealed, and its features for complexation of cyclodextrins and 18-crown-6 were considered. It was concluded that, based on the thermodynamic parameters of molecular complexation, one could judge the mode of the formation of complexes, the main driving forces of the interactions, and the degree of desolvation.

Concentration Dependent Single Chain Properties of Poly(Sodium 4-Styrenesulfonate) Subjected to Aromatic Interactions with Chlorpheniramine Maleate Studied by Diafiltration and Synchrotron-SAXS

The polyelectrolyte poly(sodium 4-styrenesulfonate) undergoes aromatic–aromatic interaction with the drug chlorpheniramine, which acts as an aromatic counterion. In this work, we show that an increase in the concentration in the dilute and semidilute regimes of a complex polyelectrolyte/drug 2:1 produces the increasing confinement of the drug in hydrophobic domains, with implications in single chain thermodynamic behavior. Diafiltration analysis at polymer concentrations between 0.5 and 2.5 mM show an increase in the fraction of the aromatic counterion irreversibly bound to the polyelectrolyte, as well as a decrease in the electrostatic reversible interaction forces with the remaining fraction of drug molecules as the total concentration of the system increases. Synchrotron-SAXS results performed in the semidilute regimes show a fractal chain conformation pattern with a fractal dimension of 1.7, similar to uncharged polymers. Interestingly, static and fractal correlation lengths increase with increasing complex concentration, due to the increase in the amount of the confined drug. Nanoprecipitates are found in the range of 30–40 mM, and macroprecipitates are found at a higher system concentration. A model of molecular complexation between the two species is proposed as the total concentration increases, which involves ion pair formation and aggregation, producing increasingly confined aromatic counterions in hydrophobic domains, as well as a decreasing number of charged polymer segments at the hydrophobic/hydrophilic interphase. All of these features are of pivotal importance to the general knowledge of polyelectrolytes, with implications both in fundamental knowledge and potential technological applications considering aromatic-aromatic binding between aromatic polyelectrolytes and aromatic counterions, such as in the production of pharmaceutical formulations.

Complexation of Cyclodextrins with Benzoic Acid in Water-Organic Solvents: A Solvation-Thermodynamic Approach

The aim of this research is to obtain new data about the complexation between β-cyclodextrin (β-CD) and benzoic acid (BA) as a model reaction of the complex formation of hydrophobic molecules with cyclodextrins (CDs) in various media. This research may help developing cyclodextrin-based pharmaceutical formulations through the choice of the appropriate solvent mixture that may be employed in the industrial application aiming to control the reactions/processes in liquid phase. In this paper, NMR results for the molecular complex formation between BA and β-CD ([BA⊂β-CD]) in D2O-DMSO-d6 and in D2O-EtOH have shown that the stability of the complex in the H2O-DMSO-d6 varies within the experimental error, while decreases in H2O-EtOH. Changes in the Gibbs energy of BA resolvation in water and water–dimethylsulfoxide mixtures have been obtained and have been used in the analysis of the reagent solvation contributions into the Gibbs energy changes of the [BA⊂β-CD] molecular complex formation. Quantum chemical calculations of the interaction energy between β-CD and BA as well as the structure of the [BA⊂β-CD] complex and the energy of β-CD and BA interaction in vacuum and in the medium of water, methanol and dimethylsulfoxide solvents are carried out. The stability of [BA⊂β-CD] complex in H2O-EtOH and H2O-DMSO solvents, obtained by different methods, are compared. The thermodynamic parameters of the [BA⊂β-CD] molecular complexation as well as the reagent solvation contributions in H2O-EtOH and H2O-DMSO mixtures were analyzed by the solvation-thermodynamic approach.

How the water-soluble hemicarcerand incarcerates guests at room temperature decoded with modular simulations

Molecular dynamics simulations of hemicarcerands and related variants allow the study of constrictive binding and offer insight into the rules of molecular complexation, but are limited because three-dimensional models of hemicarcerands are tedious to build and their atomic charges are complicated to derive. There have been no molecular dynamics simulations of the reported water-soluble hemicarcerand (Octacid4) that explain how Octacid4 encapsulates guests at 298 K and keeps them encapsulated at 298 K in NMR experiments. Herein we report a modular approach to hemicarcerand simulations that simplifies the model building and charge derivation in a manner reminiscent of the approach to protein simulations with truncated amino acids as building blocks. We also report that in aqueous molecular dynamics simulations at 298 K apo Octacid4 adopts two clusters of conformations one of which has an equatorial portal open but the guest-bound Octacid4 adopts one cluster of conformations with all portals closed. These results explain how Octacid4 incarcerates guests at room temperature and suggest that the guest-induced host conformational change that impedes decomplexation is a previously unrecognized conformational characteristic that promotes strong molecular complexation.

Molecular Complexation of Hederasaponin C with Cholesterol in Aqueous Isopropyl Alcohol

The 1:1 molecular complex of ivy triterpene glycoside hederasaponin C (HedC) with cholesterol (Chol) was obtained in aqueous isopropyl alcohol. The stability constant of (3.3 ± 0.7)∙106 (mol/L)–1 was calculated for the complex. The complexation was studied by UV- and ATR IR-Fourier spectroscopy, and method of isomolar series. The hydrogen bonds and hydrophobic interactions are formed in the molecular complex.

How a Hemicarcerand Incarcerates Guests at Room Temperature Decoded with Modular Simulations

Hemicarcerands are host molecules created to study constrictive binding with guest molecules for insights into the rules of molecular complexation. However, the molecular dynamics simulations that facilitate such studies have been limited because three-dimensional models of hemicarcerands are tedious to build and their atomic charges are complicated to derive. There have been no molecular dynamics simulations of the reported water-soluble hemicarcerand (Octacid4) that explain how it uniquely encapsulates its guests at 298 K and keeps them encapsulated at 298 K in NMR experiments. Herein we report a modular approach to hemicarcerand simulations that simplifies the model building and charge derivation in a manner reminiscent of the approach to protein simulations with truncated amino acids as building blocks. We also report that apo Octacid4 in water adopts two clusters of conformations, one of which has an equatorial portal open thus allowing guests to enter the cavity of Octacid4, in microsecond molecular dynamics simulations performed using the modular approach at 298 K. Under the same simulation conditions, the guest-bound Octacid4 adopts one cluster of conformations with all equatorial portals closed thus keeping the guests incarcerated. These results explain the unique constrictive binding of Octacid4 and suggest that the guest-induced host conformational change that impedes decomplexation is a previously unrecognized conformational characteristic that promotes strong molecular complexation.

Molecular Complex of Glycyrrhizic Acid Monoammonium Salt with Cholesterol

Background: Glycyrrhizic Acid (GA) is the major triterpene saponin of licorice roots. The most important derivative of GA is its monoammonium salt (glycyram, GC). Some pharmacological properties of triterpene saponins explain their molecular complexation with Cholesterol (Chol). However, the molecular complexation of GC with Chol has not been proven. The functional groups of GA and GC involved in the interactions with Chol were not identified. Methods: The complexation has been investigated by the method of isomolar series in the spectrophotometric version, IR, and 13C NMR spectroscopy. The constant is calculated on the basis of isomolar curves. Results: The molecular complex of GC with Chol has been prepared for the first time. It has been shown that GC forms a 1 : 1 complex with Chol having a stability constant Ks of (3.3 ± 0.2)×105 (mol/L)-1 (in 70% aqueous EtOH at 18 °С). Conclusion: Intermolecular interaction in the complex is carried out by hydrogen bond formation between C=O group of GC (in carboxyl group of the terminal residue of glucuronic acid in the carbohydrate part) and 3β-hydroxyl group of Chol: -С=О⋅⋅⋅Н-О-. Hydrophobic contacts of the aglycone part of GC with a lipophilic Chol molecule are possible.

Water-Soluble and Cytocompatible Phospholipid Polymers for Molecular Complexation to Enhance Biomolecule Transportation to Cells In Vitro

Water-soluble and cytocompatible polymers were investigated to enhance a transporting efficiency of biomolecules into cells in vitro. The polymers composed of a 2-methacryloyloxyethyl phosphorylcholine (MPC) unit, a hydrophobic monomer unit, and a cationic monomer unit bearing an amino group were synthesized for complexation with model biomolecules, siRNA. The cationic MPC polymer was shown to interact with both siRNA and the cell membrane and was successively transported siRNA into cells. When introducing 20–50 mol% hydrophobic units into the cationic MPC polymer, transport of siRNA into cells. The MPC units (10–20 mol%) in the cationic MPC polymer were able to impart cytocompatibility, while maintaining interaction with siRNA and the cell membrane. The level of gene suppression of the siRNA/MPC polymer complex was evaluated in vitro and it was as the same level as that of a conventional siRNA transfection reagent, whereas its cytotoxicity was significantly lower. We concluded that these cytocompatible MPC polymers may be promising complexation reagent for introducing biomolecules into cells, with the potential to contribute to future fields of biotechnology, such as in vitro evaluation of gene functionality, and the production of engineered cells with biological functions.