Defining permeability of curved membranes in molecular dynamics simulations.

Many phospholipid membranes in the cell have a high curvature; for instance, in caveolae, mitochondrial crystae, nanotubes, membrane pearls, small liposomes, or exosomes. Molecular dynamics (MD) simulations are a computational tool to gain insight in the transport behavior at the atomic scale. Membrane permeability is a key kinetic property that might be affected in these highly curved membranes. Unfortunately, the geometry of highly curved membranes creates ambiguity in the permeability value, even with an arbitrarily large factor purely based on geometry, caused by the radial flux not being a constant value in steady state. In this contribution, the ambiguity in permeability for liposomes is countered by providing a new permeability definition. First, the inhomogeneous solubility diffusion model based on the Smoluchowski equation is solved analytically under radial symmetry, from which the entrance and escape permeabilities are defined. Next, the liposome permeability is defined guided by the criterion that a flat and curved membrane should have equal permeability, in case these were to be carved out from an imaginary homogeneous medium. With this criterion, our new definition allows for a fair comparison of flat and curved membranes. The definition is then transferred to the counting method, which is a practical computational approach to derive permeability by counting complete membrane crossings. Finally, the usability of the approach is illustrated with MD simulations of diphosphatidylcholine (DPPC) bilayers, without or with some cholesterol content. Our new liposome permeability definition allows us to compare a spherically shaped membrane with its flat counterpart, thus showcasing how the curvature effect on membrane transport may be assessed.