Abstract
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.