To elucidate the mechanism of solute diffusion through lipid bilayer membranes, nearly 4 ns of molecular dynamics simulations of solutes in phospholipid bilayers was conducted. The study, the first atomic level study of solute diffusion in a lipid bilayer, involved four simulations of an all-atom representation of a fully solvated dimyristoylphosphatidylcholine bilayer in the La phase with benzene molecules as solutes, totalling over 7100 atoms. These simulations agreed with experimental evidence that the presence of small solutes did not affect bilayer thickness but did result in slight perturbations in the ordering of the hydrocarbon chains. At room temperature, the benzene molecules had essentially isotropic motion and rotate freely. The rate of translational diffusion varies with position within the bilayer and was faster in the center than near the zwitterionic head groups and was in excellent agreement with experimental values for the diffusion of small solutes in a bilayer. These simulations had elucidated the mechanism of diffusion in a bilayer to be similar to the "hopping" mechanism found for the diffusion of gases through soft polymers. Jumps of up to 8Å could occur in as little as 5ps whereas average motions for that time period were only ∼1.5Å. In many cases, the jumps were moderated by torsional changes in the hydrocarbon chains which served as "gates" between voids through which the benzene molecules move. Comparison of these simulations with another 1000ps simulation of benzene in a pure alkane provided evidence that lipid bilayers should not be treated as a homogeneous bulk hydrocarbon phase.

Solute Diffusion in Lipid Bilayer Membranes: an Atomic Level Study by Molecular Dynamics Simulation. Stouch, T.R.: Biochemistry, 1993, 12624-37