Given their signicance to chemical sensing and molecular recognition, host-guest interactions are of broad interest in molecular science. Cryptophanes, which are a kind of spherical cage molecules, are one of the most applicable host molecules. Herein computer simulation is used to address the binding of cryptophanes to monatomic guest species in aqueous environments. Water soluble cryptophanes have high binding anity to Xe-129, which is a powerful contrast agent for magnetic resonance imaging and can be used as an NMR-based biosensor. Molecular details of Xe-cryptophane binding are hard to obtain from experiment, however. Extensive molecular dynamics simulation are carried out to understand the underlying molecular features of the Xe-cryptophane system. Free energy perturbation and adaptive biasing force methods are used to obtain the energetic aspects of cryptophane-Xe interactions: binding anities of individual cryptophanes to Xe and potentials of mean force for Xe to entry the cavity. Additionally, the structure adjustments cryptophane undergoes as it accommodates Xe are investigated in depth. From the simulations, the hydrophobicity of cryptophane interior and the kinetics of water enter the cavity are found to be correlated with the Xe binding anity. These ndings shed light on the design of Xe-binding cryptophanes. A related cryptophane is considered for the selective binding of alkali metal ions. The cryptophane has particularly high binding anities with the large cesium cation. The Cs-137 isotope is a common, problematic radioactive nuclear ssion byproduct. The simulations provide insight on the relative anities of alkali cations and the roles of water molecules that enter the cavity along with ions. The simulations reveal that the high bind- ing anity of cryptophane to Cs+ may result from the comparatively low solvation energy of Cs+ and its geometric t to the cryptophane cavity.