Continuum solvent model studies of the interactions of an anticonvulsant drug with a lipid bilayer

Valproic acid (VPA) is a short, branched fatty acid with broad-spectrum ant iconvulsant activity. It has been suggested that VPA acts directly on the p lasma membrane. We calculated the free energy of interaction of VPA with a model lipid bilayer using simulated annealing and the continuum solvent mod el. Our calculations indicate that VPA is likely to partition into the bila yer both in its neutral and charged forms, as expected from such an amphipa thic molecule. The calculations also show that VPA may migrate (flip-flop) across the membrane; according to our (theoretical) study, the most likely flip-flop path at neutral pH involves protonation of VPA pending its insert ion into the lipid bilayer and deprotonation upon departure from the other side of the bilayer. Recently, the flip-flop of long fatty acids across lip id bilayers was studied using fluorescence and NMR spectroscopies. However, the measured value of the flip-flop rate appears to depend on the method u sed in these studies. Our calculated value of the flip-flop rate constant, 20/s. agrees with some of these studies. The limitations of the model and t he implications of the study for VPA and other fatty acids are discussed.