Membrane partition of bis-(3-hydroxy-4-pyridinonato) zinc(ii) complexes revealed by molecular dynamics simulations

The class of 3-hydroxy-4-pyridinone ligands is widely known and valuable for biomedical and pharmaceutical purposes. Their chelating properties towards biologically-relevant transition metal ions highlight their potential biomedical utility. A set of 3-hydroxy-4-pyridinone Zn(ii) complexes at different concentrations was studied for their ability to interact with lipid phases. We employed umbrella sampling simulations to attain the potential-of-mean force for a set of ligands and one Zn(ii) complex, as these permeated a 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) hydrated bilayer system. In addition, we used conventional molecular dynamics simulations to study the behavior of various Zn(ii) complexes in hydrated bilayer systems. This work discusses: (i) the partition of 3-hydroxy-4-pyridinone ligands to bilayer phases; (ii) self-aggregation in crowded environments of Zn(ii) complexes; and (iii) possible mechanisms for the membrane translocation of Zn(ii) complexes. We observed distinct interactions for the studied complexes, and distinct membrane partition coefficients (K _mem) depending on the considered ligand. The more hydrophobic ligand, 1-hexyl-3-hydroxy-2-methyl-4(1H)-pyridinone, partitioned more favorably to lipid phases (at least two orders of magnitude higher K _mem when compared to the other ligands), and the corresponding Zn(ii) complex was also prone to self-aggregation when an increased concentration of the complex was employed. We also observed that the inclusion of a coordinated water molecule in the parameterization of the Zn(ii) coordination sphere, as proposed in the available crystallographic structure of the complex, decreased the partition coefficient and membrane permeability for the tested complex.