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

Four nanoseconds molecular dynamics simulation of a nifedipine analogu e in a phospholipid bilayer was performed in order to gain insight int o the interactions of a drug molecule with the membrane and the mechan ism of drug diffusion through membranes. An all-atom representation of a fully hydrated DMPC bilayer in the La phase was employed. Such simu lations can provide detail inaccessible experimentally. It was found t hat the rate of diffusion did not vary with location in the bilayer, i n contrast to that of the much smaller benzene, which was 3 times fast er in the bilayer center than the interfacial region. Benzene diffusio n is accelerated by its ability to jump between voids in the bilayer t hat are unavailable to nifedipine due to its larger size. Toward the w ater interface the nifedipine analogue experienced a diverse environme nt including interactions with Lipid carbonyl and ''headgroup'' atoms as well as with water. On average one lipid carbonyl group and 4-6 wat er molecules interacted strongly with this molecule. Due to its motion , this environment varied during the simulation. Near the water interf ace, the preferred orientation of the drug analogue was significantly tilted relative to the bilayer normal. This differs from the orientati on often assumed for the location of drug molecules in membranes durin g interpretation of X-ray scattering studies. This tilt evolved throug h concerted changes in side-chain torsions of the solute and the orien tation of the entire solute which resulted in a significant increase i n 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 dru g and its environment. Correlation between the movement of some of lip ids and the solute suggests strong interactions or transient binding a lthough not all neighboring lipids experienced this correlation. The n ifedipine analogue did not introduce significant perturbations into th e gross properties of the bilayer.