Antibiotic activity of valinomycin Molecular dynamics simulations involving the water/membrane interface

Abstract

Molecular dynamics (MD) simulations, covering 550 ps of equilibration and 100 ps of production, of the adsorption of the antibiotic valinomycin (VM) and the dissociation reaction of its potassium complex at the two interfaces of a hydrophobic membrane bounded by water, are reported. The simulation addresses questions pertaining to the structure and behaviour of this important antibiotic in the interfacial region and represent the first study of ion decomplexation at an atomistically detailed interface. The system involves a total of 18866 atomic sites, including four VM molecules and four complexes. The simulation shows uncomplexed VM to be a surfactant. Owing to the flexibility of the VM ring the uncomplexed molecule readily adopts novel conformations at the interface with non-polar groups embedded in the membrane and the carbonyl groups hydrogen bonded with water. These conformations are quite distinct from those seen in the solid state or in bulk solution. The observed flattening of the molecule against the interface is in excellent accord with experimental measurements of molecular shape at the water/air interface and on the surface of lipid bilayers. Although complex formation with K + ions is not observed on the timescale of the simulation, the decomplexation reaction occurs spontaneously on a timescale of 20–30 ps and shows noticeable orientation effects. At the interface, the K + is selectively released through the Lac face of the bracelet-like complex, in contrast to release through the HyV face in aqueous or methanol solution. At the interface, the release mechanism consists of the gradual replacement of ester carbonyl groups by water molecules in the first coordination sphere of K + . The evidence from the simulation suggests that the rate-determining step for decomplexation is the orientational ordering of the complex at the interface and not the formation of intermediate water adducts.