ANTIBIOTIC-ACTIVITY OF VALINOMYCIN - MOLECULAR-DYNAMICS SIMULATIONS INVOLVING THE WATER MEMBRANE INTERFACE/

Molecular dynamics (MD) simulations, covering 550 ps of equilibration and 100 ps of production, of the adsorption of the antibiotic valinomy cin (VM) and the dissociation reaction of its potassium complex at the two interfaces of a hydrophobic membrane bounded by water, are report ed. 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 de tailed interface. The system involves a total of 18 866 atomic sites, including four VM molecules and four complexes. The simulation shows u ncomplexed VM to be a surfactant. Owing to the flexibility of the VM r ing the uncomplexed molecule readily adopts novel conformations at the interface with non-polar groups embedded in the membrane and the carb onyl groups hydrogen bonded with water. These conformations are quite distinct from those seen in the solid state or in bulk solution. The o bserved flattening of the molecule against the interface is in excelle nt accord with experimental measurements of molecular shape at the wat er/air interface and on the surface of lipid bilayers. Although comple x formation with K+ ions is not observed on the timescale of the simul ation, the decomplexation reaction occurs spontaneously on a timescale of 20-30 ps and shows noticeable orientation effects. At the interfac e, 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 molecule s in the first coordination sphere of K+. The evidence from the simula tion suggests that the rate-determining step for decomplexation is the orientational ordering of the complex at the interface and not the fo rmation of intermediate water adducts.