Molecular dynamics and free energy perturbation studies of Ca2+/Sr2+ complexation selectivities of the macrocyclic ionophores DOTA and TETA in water

Abstract

Molecular dynamics simulations have been performed on the uncomplexed tetraanionic macrocyclic ionophores DOTA I and TETA II and on their complexes with Ca²⁺ and Sr²⁺ cations in the gas phase and in water. We have found that for both ligands, the most stable complex is the one where the cation is completely encapsulated in a pseudocavity formed by four nitrogens and four oxygens (one per carboxylate group). All stereoisomers for this type of complex have similar coordination and hydration patterns. Water molecules do not coordinate to the cation when it is encapsulated by the ligand but form hydrogen bonds with non-coordinating carboxylic oxygens, leading to repulsive interactions with the cation. The higher binding affinity of I compared to II for Ca²⁺ is explained by better preorganization of I for complexation. Free energy perturbation simulations performed on I·M²⁺ and II·M²⁺ complexes show that the preference of both ligands for Ca²⁺ over Sr²⁺ in water results from their higher intrinsic binding affinities for Ca²⁺ rather than the difference between hydration energies of the uncomplexed cations.