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

Molecular dynamics simulations have been performed on the uncomplexed tetra anionic macrocyclic ionophores DOTA I and TETA II and on their complexes wi th 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 co mpletely encapsulated in a pseudocavity formed by four nitrogens and four o xygens (one per carboxylate group). All stereoisomers for this type of comp lex have similar coordination and hydration patterns. Water molecules do no t coordinate to the cation when it is encapsulated by the ligand but form h ydrogen bonds with non-coordinating carboxylic oxygens, leading to repulsiv e interactions with the cation. The higher binding affinity of I compared t o II for Ca2+ is explained by better preorganization of I for complexation. Free energy perturbation simulations performed on I . M2+ and II . M2+ com plexes show that the preference of both ligands for Ca2+ over Sr2+ in water results from their higher intrinsic binding affinities for Ca2+ rather tha n the difference between hydration energies of the uncomplexed cations.