Solid-State and Solution Structure of the Salinomycin−Sodium Complex: Stabilization of Different Conformers for an Ionophore in Different Environments

Abstract

The conformation of the ionophore−metal complex between salinomycin and sodium was determined in solid state and in solution using X-ray single-crystal structure analysis and a combined approach of 2D-NMR spectroscopy with restrained simulated annealing calculations. The solution structure of the salinomycin−Na complex was studied in two different solvents (DMSO-d6 and CDCl3) in order to focus on conformational differences in various molecular environments. The X-ray structure of the complexed salinomycin is characterized by two separate conformers found in the asymmetric unit with a similar coordination of the central sodium ion buried in the interior, hydrophilic region of this ionophore. A quasi-macrocyclic core structure is stabilized by numerous metal−oxygen electrostatic interactions and by an intramolecular head-to-tail hydrogen bond. The NMR structure in CDCl3 is very similar to those two conformations in the solid state, while the structure in DMSO differs significantly. It could be demonstrated that previously published NMR data in CDCl3 do not define a unique conformational state with sufficient accuracy, while this was possible using our own NMR derived datasets discussed herein. For conformer classification and comparison, steric field descriptors based on the CoMFA methodology are used in conjunction with a principal component analysis to uncover the most relevant structural differences between individual salinomycin−Na structures. These studies provided insight into the specific requirements of metal binding for this important polyether ionophore, which could serve as a model system for studying ion transport across biological membranes. Different environments tend to stabilize different conformations of the outer sphere, while the complexation pattern and the geometry of the coordination sphere of the sodium ion remains unaffected.