Permeability of Small Molecules through a Lipid Bilayer: A Multiscale Simulation Study

Abstract

The transmembrane permeation of eight small (molecular weight <100) organic molecules across a phospholipid bilayer is investigated by multiscale molecular dynamics simulation. The bilayer and hydrating water are represented by simplified, efficient coarse-grain models, whereas the permeating molecules are described by a standard atomic-level force-field. Permeability properties are obtained through a refined version of the z-constraint algorithm. By constraining each permeant at selected depths inside the bilayer, we have sampled free energy differences and diffusion coefficients across the membrane. These data have been combined, according to the inhomogeneous solubility-diffusion model, to yield the permeability coefficients. The results are generally consistent with previous atomic-level calculations and available experimental data. Computationally, our multiscale approach proves 2 orders of magnitude faster than traditional atomic-level methods.

Permeation of the three aromatic dipeptides through lipid bilayers: Experimental and computational study

“…Several studies for small molecules do report increased diffusion rates at the center of the lipid bilayer. 15,[18][19][20][21] In contrast, most studies of larger molecules that are at least the size of the amino acids studied in this work show relatively flat diffusion profiles in homogenous lipid bilayers. 25,27,30 Thus, our translational diffusion results are consistent with other reported values for larger molecules.…”

“…Our PMF profile for NATA qualitatively agrees with results of Cardenas et al, 43 and the calculated translational and rotational diffusion rates in the solution region agree with both computational results and experimental data. 15,[18][19][20][21]25,27,30 Thus, we believe that our combined experimental and computational study provides improved understanding of the process of transmembrane permeation of small aromatic peptides. Especially valuable are the microscopic insights from the simulations, including the large difference between translational and rotational diffusion rates and changes in peptide structure as a function of membrane insertion depth.…”

“…Previous studies, which focused on translational dynamics, typically found faster motions in the central region of lower relative density. 15,[18][19][20][21] Presence of slow reorientations in the course of membrane transport has been previously explored. 25,27,30 Our simulations suggest that translational diffusion in the z direction, along the elongated lipid molecules, is relatively easy; while rotational diffusion of the peptide sidechains, which are tethered to their backbones and must move in directions perpendicular to the tightly packed lipids, is unexpectedly slow.…”

“…14 Recent molecular dynamics studies have focused on a wide variety of molecules passively diffusing through membranes, such as water, [15][16][17] small molecules, [18][19][20][21][22][23] model drug compounds, 6,22,24,25 analgesics, [26][27][28] drug delivery systems, 29,30 dyes, 31,32 other lipids, 33,34 nanoparticles, [35][36][37] toxins, 38 small peptides, 39,40 and even transmembrane proteins. 41,42 However, only a handful of MD studies have examined amino acid-related systems and are confined to tryptophan, [43][44][45] arginine, 46,47 lysine, 47 and amino acid analogues.…”

Comparative assessment of the ELBA coarse-grained model for water

“…SSD is a model consisting of a Lennard-Jones sphere, a point dipole, and an additional octupolar term aimed at reproducing hydrogen bonding. SSD has been used to study liquid water and ice [80][81][82][83], and as a solvent in various systems [80,[84][85][86][87][88][89]. In Table 7 we collect results obtained from various slightly different parametrisations of the SSD force field reported in the literature; good agreement with the experiment can be noticed in terms of bulk properties.…”