This study extended previous studies of the mechanism of small molecule diffusion through lipid membranes. Atomic level molecular dynamics simulations of over 4 ns of benzene in fully hydrated dimyristoylphosphatidylcholine (DMPC) bilayers were performed at four different temperatures above the gel-to-Lα phase transition temperature. These studies confirmed previous observations that small solutes diffused at different rates in different locations in the bilayer. This difference in diffusion was likely to be due to "jumps" (single, large movements) between voids which were most common in the center of the bilayer. The benzene molecules appeared to favor different regions of the bilayer at different temperatures. Although at 320K the solutes showed no regional preference, at 310K they migrate to the center of the bilayer, while at 340K they reside mostly near the head group region. This correlated with the distribution of free volume which concentrates at the bilayer center at low temperature but became more diffuse at higher temperatures. The mechanism of the diffusional process was found to be complex. Not only did the rate of diffusion depended upon location within the bilayer, but the characteristics of this process appeared to respond to temperature changes differently in the different regions of the bilayer. Only short time motions were dependent directly on the temperature. Longer time motions depended additionally on the size and availability of voids and the rate of torsional isomerisation of the lipid molecules. It was found that an increase in kinetic energy was not always coincident with a jump; some jumps may be passive processes. This study provided further evidence that the interior of lipid bilayer membranes was not a homogeneous system analogous to pure alkane. Rather it was a structured system with different properties depending on the distance from the lipid/water interface.Mechanism of Solute Diffusion through Lipid Bilayer Membranes by Molecular Dynamics Simulation. Bassolino-Klimas, D., Alper, H.E., Stouch, T.R.: Journal of the American Chemical Society, 1995, 117[14], 4118-29