Solute diffusion in lipid bilayer membranes: An atomic level study by molecular dynamics simulation

Abstract

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 (DMPC) bilayer in the L alpha phase with benzene molecules as solutes, totaling over 7100 atoms. These simulations agree with experimental evidence that the presence of small solutes does not affect bilayer thickness but does result in slight perturbations in the ordering of the hydrocarbon chains. At room temperature, the benzene molecules have essentially isotropic motion and rotate freely. The rate of translational diffusion varies with position within the bilayer and is faster in the center than near the zwitterionic headgroups and is in excellent agreement with experimental values for the diffusion of small solutes in a bilayer. These simulations have 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 8 A can occur in as little as 5 ps whereas average motions for that time period are only approximately 1.5 A. In many cases, the jumps are moderated by torsional changes in the hydrocarbon chains which serve as "gates" between voids through which the benzene molecules move. Comparison of these simulations with another 1000-ps simulation of benzene in a pure alkane provides evidence that lipid bilayers should not be treated as a homogeneous bulk hydrocarbon phase.

Some substrates of P-glycoprotein targeting <i>β</i>-amyloid clearance by quantitative structure-activity relationship (QSAR)/membrane-interaction (MI)-QSAR analysis

“…When the value of PSA of a molecule lessened within the range from 0 to 108.80 Å 2 , its value of LogBB would increase. This was consistent with the experimental results that the more polarity it possessed, the more difficultly a molecule entered the hydrophobic environment of BBB [38]. BI as the connective index of molecular average total distance pertained to the volume parameter.…”

“…A model of DMPC monolayer membrane composed of 25 DMPC molecules (5 × 5 × 1) was constructed using Material Studio and minimized for 200 steps with the smart minimizer. Here, the parameter of the single crystal of DMPC with a = 8 Å, b = 8 Å, and γ = 96.0˚ resulted in each lipid molecule with an average area of 64Å 2 similar to Stouch's research results [38]. Moreover, a layer of water (40 × 40 × 10 Å 3 ) including 529 water molecules was added to the polar side of the DMPC monolayer membrane (Figure 1).…”

Multiscale Modeling Framework of Transdermal Drug Delivery

“…Since the early 1990s molecular dynamics studies of diffusion of small molecules in lipid bilayers have been extensively pursued. 2,5,6,29 These studies have shown that small solutes diffuse at different rates depending on their location in the bilayer, with high diffusion rates found in the center of the bilayer, where the membrane density is low, while much lower diffusion rates were found in the region of the headgroups. In order to get a more detailed description of the position-dependence of the diffusion process, a series of simulations of dipalmitoylphosphatidylcholine (dppc) and dmpc lipids systems were performed with a single fentanyl molecule and different numbers of oleic acid molecules, where the fentanyl molecule is constrained in the z-direction (normal to the bilayer) to certain depths in the bilayer, while still being free to move in the xy plane.…”

The Role of Size and Charge for Blood–Brain Barrier Permeation of Drugs and Fatty Acids

“…The diffusion of small hydrophobic non-electrolytes such as benzene is too fast to be measured but was investigated by molecular dynamics simulations (Bassolino-Klimas et al 1993). After insertion into the well-ordered, highly packed interfacial lipid region of the membrane (which was the ratelimiting step), benzene was shown to move from one packing defect to the next, whereby the rate of diffusion increased with increasing cis-trans isomerization of the fatty acyl chains toward the center of the membrane.…”