Hydration of the 222 cryptand and 222 cryptates studied by molecular dynamics simulations

International audienceSolvent effects and structure of ionophores in solution are felt to be essential for determining their binding selectivity, solubility, or transport capability, but these are generally not precisely known. We report here a theoretical study, using molecular dynamics simulations, on a prototypical system: the bicyclic 222 cryptand in water, either in its free state or with complexed cations (from Li+ to Cs+, Ca2+, and Eu3+) with explicit representation of the solvent. It is found that the uncomplexed 222, which is neither conformationally organized in the solid state nor in the gas phase for cation complexation, adopts in water preferentially a conformation suitable for ionophoric behavior. This conformer, which presents a cavity with converging binding sites and a diverging “hydrophobic skin”, has no water inside. It is stabilized by three interbridging water molecules forming an arrangement of C3 symmetry. Alternative forms, in which nitrogen or oxygen binding sites are diverging and more accessible to the solvent, are less well hydrated. We suggest that “solvent-induced preorganization” can occur in other macro(poly)cyclic systems with gauche XC-CX (X = N, O) arrangements of suitable topology. For the cation complexes, we investigate the effectiveness of solvent shielding by the ionophore for encapsulated cations of increasing size (from Li+ to Cs+) or charge (in the Na+, Ca2+, Eu3+ series). There are both direct cation-water coordination and longer range cation-water interactions of increasing importance as the cationic charge increases. Particularly, the coordination number of Eu3+ calculated for the Eu3+/222 cryptate (3.9) agrees well with experimental values. This microscopic description of the hydration pattern allows for reinterpretation of several experimental results and provides deeper insights into dynamical features and solvation effects on molecular recognition