Molecular Dynamics Simulations of Membrane Permeability

Abstract

This Review illustrates the evaluation of permeability of lipid membranes from molecular dynamics (MD) simulation primarily using water and oxygen as examples. Membrane entrance, translocation, and exit of these simple permeants (one hydrophilic and one hydrophobic) can be simulated by conventional MD and permeabilities can be evaluated directly by Fick's First Law, transition rates, and a global Bayesian analysis of the inhomogeneous solubility-diffusion model. The assorted results, many of which are applicable to simulations of non-biological membranes, highlight the limitations of the homogeneous solubility diffusion model; support the utility of inhomogeneous solubility diffusion and compartmental models; underscore the need for comparison with experiment for both simple solvent systems (such as water/hexadecane) and well characterized membranes; and demonstrate the need for microsecond simulations for even simple permeants like water and oxygen. Undulations, subdiffusion, fractional viscosity dependence, periodic boundary conditions, and recent developments in the field are also discussed. Lastly, while enhanced sampling methods and increasingly sophisticated treatments of diffusion add substantially to the repertoire of simulation-based approaches, they do not address directly the critical need for force fields with polarizability and multipoles, and constant pH methods.

Lipidomic and biophysical homeostasis of mammalian membranes in response to dietary lipids is essential for cellular fitness

“…Although biophysical membrane perturbations likely have several distinct physiological effects, we considered the central role of the plasma membrane as a selective barrier. Significant computational and model membrane literature 64,65 suggests that membrane permeability is dependent on lipid composition, with more loosely packed, fluid membranes being more permeable to various polar and amphiphilic compounds. Simulations have specifically analyzed polyunsaturated phospholipids, showing DHA-containing membranes are 2-3-fold more permeable than monounsaturated counterparts 64 .…”

“…Significant computational and model membrane literature 64,65 suggests that membrane permeability is dependent on lipid composition, with more loosely packed, fluid membranes being more permeable to various polar and amphiphilic compounds. Simulations have specifically analyzed polyunsaturated phospholipids, showing DHA-containing membranes are 2-3-fold more permeable than monounsaturated counterparts 64 . Thus, we hypothesized that the permeability of cell membranes would be increased by incorporation of polyunsaturated lipids.…”

Prediction of Passive Membrane Permeability by Semi‐Empirical Method Considering Viscous and Inertial Resistances and Different Rates of Conformational Change and Diffusion

“…The solute can pass through the membrane before the conformational ensemble of the solute reaches equilibrium distribution (see Figure 1A). [4] In this case, the distribution of solute is different from the distribution coefficient D observed in equilibrium.…”

“…[4][5][6][7][8][9][10][11][12][13][14][15] In these calculations, MD simulations have been applied to explicit atomic models of membrane molecules with solvent water molecules. [4][5][6][7][8][9][10][11][12][13][14][15] In these calculations, MD simulations have been applied to explicit atomic models of membrane molecules with solvent water molecules.…”

“…Recent advances in molecular dynamics (MD) simulations enable the understanding and evaluation of trans-cellular passive permeability. [4][5][6][7][8][9][10][11][12][13][14][15] In these calculations, MD simulations have been applied to explicit atomic models of membrane molecules with solvent water molecules. Since permeation is a very slow process, biased MD simulations have been popular in this analysis.…”