Molecular dynamics simulations of ethanol permeation through single and double-lipid bilayers

Abstract

Permeation of small molecules through membranes is a fundamental biological process, and molecular dynamics simulations have proven to be a promising tool for studying the permeability of membranes by providing a precise characterization of the free energy and diffusivity. In this study, permeation of ethanol through three different membranes of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylserine (POPS), POphosphatidylethanolamine (POPE), and PO-phosphatidylcholine (POPC) is studied. Permeabilities are calculated and compared with two different approaches based on Fick's first law and the inhomogeneous solubility-diffusion model. Microsecond simulation of double bilayers of these membranes provided a direct measurement of permeability by a flux-based counting method. These simulations show that a membrane of POPC has the highest permeability, followed by POPE and POPS. Due to the membrane-modulating properties of ethanol, the permeability increases as functions of concentration and saturation of the inner leaflet in a double bilayer setting, as opposed to the customary definition as a proportionality constant. This concentration dependence is confirmed by single bilayer simulations at different ethanol concentrations ranging from 1% to 18%, where permeability estimates are available from transition-based counting and the inhomogeneous solubilitydiffusion model. We show that the free energy and diffusion profiles for ethanol lack accuracy at higher permeant concentrations due to non-Markovian kinetics caused by collective behavior. In contrast, the counting method provides unbiased estimates. Finally, the permeabilities obtained from single bilayer simulations are combined to represent natural gradients felt by a cellular membrane, which accurately models the non-equilibrium effects on ethanol permeability from single bilayer simulations in equilibrium.

Membrane thickness, lipid phase and sterol type are determining factors in the permeability of membranes to small solutes

“…Also, for higher concentrations, the ISD model does not capture the collective behavior of the permeating solute and its effects on the membrane. However, for compounds at low concentrations the estimates of the permeability coefficients from the ISD model are comparable to the unbiased estimates from transition-based counting 72 . Further studies on the permeability of small solutes through lipid membranes and the ISD in various scenarios are provided in the references 16 , 71 – 74 .…”

“…The permeation dynamics is assumed to be diffusive in the ISD model. Deviations from such an assumption may lead to inaccurate estimates of the permeability coefficients for permeants that interact strongly with one another or with the membrane 71 , 72 . Also, for higher concentrations, the ISD model does not capture the collective behavior of the permeating solute and its effects on the membrane.…”

Membrane thickness, lipid phase and sterol type are determining factors in the permeability of membranes to small solutes

“…Also, for higher concentrations, the ISD model does not capture the collective behavior of the permeating solute and its effects on the membrane. However, for compounds at low concentrations the estimates of the permeability coefficients from the ISD model are comparable to the unbiased estimates from transition-based counting 68 . Further studies on the permeability of small solutes through lipid membranes and the ISD in various scenarios are provided in the references 16,[67][68][69][70] .…”

“…The permeation dynamics is assumed to be diffusive in the ISD model. Deviations from such an assumption may lead to inaccurate estimates of the permeability coefficients for permeants that interact strongly with one another or with the membrane 67,68 . Also, for higher concentrations, the ISD model does not capture the collective behavior of the permeating solute and its effects on the membrane.…”

Impact of Surface Polarity on Lipid Assembly under Spatial Confinement

“… 36 , 44 − 47 For POPC specifically, it has been shown that ethanol has high permeability and aggregates at the hydrophilic/phobic interface. 44 , 45 Shobhna and Kashyap 47 show that at significantly higher ethanol-to-lipid ratio vesicles still retain structures. When analyzing snapshots of solvent permeability ( Figures S3–S5 ), we observe evidence consistent with these trends of thinning, pore formation, and high permeability across POPC bilayers, as well as ethanol aggregation at the hydrophilic/phobic interface.…”