Quantitative prediction of physical properties of liquids is important for many applications. Computational methods based on either explicit or implicit solvent models can be used to approximate thermodynamics properties of liquids. Here, we evaluate the predictive power of implicit solvent models for solvation free energy of organic molecules in organic solvents. We compared the results calculated with four generalized Born (GB) models (GB^Still, GB^HCT, GB^OBCI, and GB^OBCII), the Poisson–Boltzmann (PB) model, and the density-based solvent model SMD with previous solvation free energy calculations (Zhang et al. J. Chem. Inf. Model. 2015, 55, 1192–1201) and experimental data. The comparison indicates that both PB and GB give poor agreement with explicit solvent calculations and even worse agreement with experiments (root-mean-square deviation ≈ 15 kJ/mol). The main problem seems to be the prediction of the apolar contribution, which should include the solvent entropy. The quantum mechanical-based SMD model gives significantly better agreement with experimental data than do PB or GB, but it is not as good as explicit solvent calculation results. The dielectric constant ε of the solvent is found to be a powerful predictor for the polar contribution to the free energy in implicit models; however, the Onsager relation may not hold for realistic solvent, as suggested by explicit solvent and SMD calculations. From the comparison, we also find that with an optimization of the apolar contribution, the PB model gives slightly better agreement with experiments than the SMD model, whereas the correlation between the optimized GB models and experiments remains poor. Further optimization of the apolar contribution is needed for GB models to be able to treat solvents other than water.

The conformational stability and activity of Candida antarctica lipase B (CALB) in the polar and nonpolar organic solvents were investigated by molecular dynamics and quantum mechanics/molecular mechanics simulations. The conformation change of CALB in the polar and nonpolar solvents was examined in two aspects: the overall conformation change of CALB and the conformation change of the active site. The simulation results show that the overall conformation of CALB is stable in the organic solvents. In the nonpolar solvents, the conformation of the active site keeps stable, whereas in the polar solvents, the solvent molecules reach into the active site and interact intensively with the active site. This interaction destroys the hydrogen bonding between Ser¹⁰⁵ and His²²⁴. In the solvents, the activation energy of CALB and that of the active site region were further simulated by quantum mechanics/molecular mechanics simulation. The results indicate that the conformation change in the region of active sites is the main factor that influences the activity of CALB.

The structure of the inclusion complexes of β-cyclodextrin (β-CD) with daidzein and daidzin in D₂O were investigated using NMR spectroscopy. For the β-CD and daidzein system, two types of 1:1 complexes were formed with the daidzein deeply inserted into the CD cavity with different orientations. For the β-CD/daidzin system, a 1:1 complex was formed with the flavonoid part of daidzin entering the CD cavity from the wide rim. The inclusion complexes determined by NMR were constructed using molecular docking. Furthermore, the mixture of puerarin, daidzein and daidzin, which are the major isoflavonoid components present in Radix puerariae, was analyzed by diffusion-ordered spectroscopy (DOSY) alone and upon addition of β-CD in order to mimic chromatographic conditions and compare their binding affinities.

Electrostatic and van der Waals interactions as well as entropy contribute to the energetics governing macromolecular complexation in biomolecules. Hydrogen bonds play a particularly important role in such interactions. Here we use molecular dynamics (MD) simulations to investigate the hydrogen bond (HB) orientations of free beta-cyclodextrin (β-CD) and head-to-head dimerization of β-CD monomers with and without guest molecules in different environments, namely, in 10 different solvents covering a wide range of polarity. Potentials of mean force for the dimer dissociation are derived from umbrella sampling simulations, allowing determination of the binding affinity between monomers. The HB orientations are in good agreement with available experimental data in water and dimethyl sulfoxide, yielding confidence in the force field used. HB exchanges at the secondary rim of β-CD are observed with a fast rate in water and with a low rate or even no exchange in other solvents. Orientational preferences of interglucopyranose HBs and their effects on the β-CD structure in these solvents are discussed in detail. Polar solvents with stronger HB accepting abilities can interrupt intermolecular HBs more easily, resulting in a less stable dimer. Guest molecules included in the channel-type cavity strengthen the binding affinity between two monomers to some extent, particularly in polar solvents. Formation of the head-to-head dimer is therefore solvent-dependent and guest-modulated. There is only limited correlation between the dimer binding energies and solvent properties like the dielectric constant. This implies that implicit solvent models will not be capable of predicting important properties like binding energy for other solvents than water without a complete reparameterization. This work provides a deeper comprehension on the properties of β-CD, and implications for the application of cyclodextrins in aqueous and nonaqueous media are discussed.