ORIENTATION AND DIFFUSION OF A DRUG ANALOG IN BIOMEMBRANES - MOLECULAR-DYNAMICS SIMULATIONS

Four nanoseconds molecular dynamics simulation of a nifedipine analogue in a phospholipid bilayer was performed in order to gain insight into the interactions of a drug molecule with the membrane and the mechanism of drug diffusion through membranes. An all-atom representation of a fully hydrated DMPC bilayer in the La phase was employed. Such simulations can provide detail inaccessible experimentally. It was found that the rate of diffusion did not vary with location in the bilayer, in contrast to that of the much smaller benzene, which was 3 times faster in the bilayer center than the interfacial region. Benzene diffusion is accelerated by its ability to jump between voids in the bilayer that are unavailable to nifedipine due to its larger size. Toward the water interface the nifedipine analogue experienced a diverse environment including interactions with Lipid carbonyl and ''headgroup'' atoms as well as with water. On average one lipid carbonyl group and 4-6 water molecules interacted strongly with this molecule. Due to its motion, this environment varied during the simulation. Near the water interface, the preferred orientation of the drug analogue was significantly tilted relative to the bilayer normal. This differs from the orientation often assumed for the location of drug molecules in membranes during interpretation of X-ray scattering studies. This tilt evolved through concerted changes in side-chain torsions of the solute and the orientation of the entire solute which resulted in a significant increase in the hydrogen bonding of the solute with the lipids and (especially) water. This implies that an important contribution to the behavior of drugs in membranes is optimization of hydrogen bonding between the drug and its environment. Correlation between the movement of some of lipids and the solute suggests strong interactions or transient binding although not all neighboring lipids experienced this correlation. The nifedipine analogue did not introduce significant perturbations into the gross properties of the bilayer.