Influence of Water/Ethanol Mixing Ratio on Gemcitabine Binding to Cucurbit-7-uril Based on Molecular Dynamics Simulations and Three-Dimensional Reference Interaction Site Model.

Accurate binding affinities of the cucurbit-7-uril-gemcitabine (CB7-GEM) complex in pure water and ethanol/water-mixed solvents were obtained by combining molecular dynamics simulations and three-dimensional reference interaction site model (3D-RISM) calculations. Point charges of CB7 and GEM molecules, depending on solvent mixture ratios, were determined using 3D-RISM self-consistent field (3D-RISM-SCF) calculations. The calculated binding affinities reveal that the most preferable CB7-GEM complex forms in the pure water system. The complexes in the mixed solvents show lower stability at higher ethanol ratios. Stable conformations at different solvent concentrations appear to be a key factor in the obtained trend of binding affinity enhancement. Conformations in the high-water fractions, associated with higher complex stability, exhibit lower internal energies than those in high-methanol fractions. Disruption of hydrogen-bonding formation also plays a crucial role in the solvation free energies. An explicit solvent model is crucial for accurate calculations of CB7-GEM complexes in these binary mixtures, providing results comparable to the experiments.