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), PO-phosphatidylethanolamine (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 solubility-diffusion 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.